UA122100C2 - Diacylglycerol acyltransferase 2 inhibitors - Google Patents

Abstract

Compounds of Formula (I) that inhibit the activity of the diacylglycerol acyltransferase 2 (DGAT2) and their uses in the treatment of diseases linked thereto in animals are described herein. (I)

Description

FIELD OF THE INVENTION

The invention relates to new pharmaceutical compounds, pharmaceutical compositions containing these compounds, and their use for inhibiting the activity of diacylglycerol acyltransferase 2 (pROATg).

PREREQUISITES FOR THE CREATION OF THE INVENTION

Triglycerides or triacylglycerols (TACs) are the main form of energy storage in mammals.

TACs are formed by successive esterification of glycerol with three fatty acids of different chain length and degree of saturation (1). TAC synthesized in the intestine or liver are packaged into chylomicrons or very low-density lipoprotein (VLDL), respectively, and exported to peripheral tissues, where they are hydrolyzed to their constituent fatty acids and glycerol by lipoprotein lipase (LIPL). The resulting non-esterified fatty acids (NFA) can either be further metabolized for energy production or transesterified and stored.

Under normal physiological conditions, high-energy-density TAC remains sequestered in various fat depots until there is a demand for its release, after which it is hydrolyzed to glycerol and free fatty acids, which are then released into the bloodstream. This process is strictly regulated by the opposition to the action of insulin and hormones, such as catecholamines, which contribute to the deposition and mobilization of TAC reserves in various physiological conditions. In postprandial conditions, insulin acts to inhibit lipolysis, thereby restraining the release of energy in the form of nonfatty fatty acids and ensuring proper storage of dietary lipids in adipose depots. However, in patients with type 2 diabetes, the ability of insulin to inhibit lipolysis is enhanced and the NEC, which is excessively secreted from adipocytes, is unacceptably elevated.

This, in turn, results in increased lipid delivery to tissues such as muscle and liver. In the absence of energy demand, TAC and other lipid metabolites such as diacylglycerol (DAC) can accumulate and cause loss of insulin sensitivity (2).

Insulin resistance in muscle is characterized by reduced glucose uptake and glycogen deposition, while in the liver, loss of insulin signaling leads to dysregulated glucose production and overproduction of TAC-rich

LIIDNSH, a characteristic feature of type 2 diabetes (3). Increased secretion of TAS enriched LLDNSHTC,

Of the so-called LDL particles, it is believed to stimulate the production of small, dense low-density lipoprotein (LDL), a proatherogenic subfraction, LDL, which is associated with an increased risk of coronary heart disease (4).

Diacylglycerol acyltransferases (DACs) catalyze the final stage in the synthesis of TAC, in particular, the esterification of a fatty acid with diacylglycerol, which ultimately leads to the formation of TAC. Two types of OSAT enzymes (OBATI1 and OSAT) have been characterized in mammals.

Although these enzymes catalyze the same enzymatic reaction, their corresponding amino acid sequences are unrelated and occupy different gene families. Mice carrying a disruption in the gene encoding OSATI are resistant to diet-induced obesity and have increased energy expenditure and activity (5). Yudai-/- mice exhibit dysregulated afternoon chylomicron release and lipid accumulation in enterocytes (6). The metabolically dominant phenotype observed in these mice is thought to be due to the loss of expression of OSATI in the intestine (7). It is important to note that, despite the defect in lactation in female Odai1-/- mice, these animals retain the ability to synthesize TAC, which indicates the existence of additional OBAT enzymes. This observation and isolation of a second OAT from the fungus Mogiigea gattapiapa led to the identification and characterization of OAT (8). raATa is mostly expressed in the liver and adipose tissue, and unlike OSATI, it shows a strong substrate specificity for ALS (8). Deletion of the OSATAO gene in rodents results in defective intrauterine development, severe lipemia, impaired skin barrier function, and early postnatal death (9). Because of the lethality caused by loss of USAT2, much of our understanding of the physiological role of USAT2 comes from studies using antisense oligonucleotides (OR) in rodent models of metabolic disease. In this context, inhibition of hepatic OSAT2 results in improved plasma lipoprotein profile (reduced total cholesterol and TAC) and reduced hepatolipid burden, which is accompanied by improved insulin sensitivity and whole-body glucose control (10-12). Although the molecular mechanisms that underlie these observations are not yet fully elucidated, it is clear that the inhibition of ОХОСАТ2 will result in the negative regulation of the expression of a number of genes that encode proteins involved in lipogenesis, including proteins 1c that bind sterol regulatory elements (ZKEVRIs ) and stearoyl CoA desaturase 1 (С5СО1) (11, 12). because in parallel with this, oxidative pathways are stimulated, as evidenced by an increase in gene expression,

such as carnitine palmitoyltransferase 1 (CPT1) (11). The overall result of these changes is a reduction in hepatic CAC and TAC lipid levels, which in turn leads to improved hepatic insulin sensitivity. In addition, inhibition of OSAT2 suppresses TAC secretion of hepatic VLDL and reduces circulating cholesterol levels. Finally, plasma levels of apolipoprotein B (APO) were suppressed, possibly due to a decrease in the supply of TAC for lipidation of newly synthesized APO protein (10, 12). The positive results from OSAT2 inhibition on both glycemic control and plasma cholesterol profile support that this target may be valuable in the treatment of metabolic disease (11). In addition, the observation that inhibition of USAT2 activity results in reduced hepatic lipid accumulation suggests that inhibitors of this enzyme may have applications in the treatment of nonalcoholic steatohepatitis (NAH), a very common liver disease characterized by excess fat deposition in the liver

In recent years, several low molecular weight inhibitors of OS/AT2 have been reported in the literature (13-19) and patent applications (М/О2013150416, М/О2013137628, 0520150259323, мМО2015077299, ШМО2016036633, УМО2016036638, УМО2016036603). 1. Soietap, V. A., apa 0. sch. Maznek 2011. Snet Vem 111: 6359-6386. 2. Epiop, 0. M., apa a. I. ZpyItap. 2010. Mai Mea 16: 400-402.

Z. Spoi, 5. N., apa N. M. Siiperegu. 2011. Ttepavz Epdosiipoi Meiab 22: 353-363. 4. BI-Rieite, A. bS.ei.aI. 2005. Apetiozsiei Titotr Mavss Vioi! 25: 553-559. 5. DRINK, 5. u. eh AI... 2000. Mai Sepei 25: 87-90. 6. Vyptan, K. K. ei.ai. 2002. In Viol Snet 277: 25474-25479. 7. I ee, V., A. M. ei.ai. 2010. In Giria Res 51: 1770-1780. 8. Mep, 0. Y. ei.aI. 2008. In Iria Res 49: 2283-2301. 9. Biope, 5. U. ei.aI. 2004. U) Vioi Snet 279: 11767-11776. 10. Pi, U. eia)I. 2008. Viospit Viorpuz Asia 1781: 97-104. 11. Spoi, b. 5. egaiI. 2007. In Biol Speth 282: 22678-22688. 12. We, H. H.eiaI. 2005. Neurology 42: 362-371. 13. ОЙ, y. hey 9. Iiria. Rev. 2012, 53 (6), 1106-16. 14. M/igov, N. V. ei.aI. REV5. IN). 2012, 279 (17), 3033-47;

From 15. Kit, M. O. ей.а)й. Vioi Rnagt. Wow 2013, 36 (7), 1167-73 16. I ee, K. eiaI. Oh Viotoi Snet 2013, 11 (5), 849-58 17. Kit, M. 0. ей.а)й. VioI. Rnagt. Wow 2014, 37 (10), 1655-1660. 18. Rshaividi, K. ei.a)I. In May Speth 2015, 58 (18), 7173-85. 19. Itrpdiyo, 4. E. eiai. U. Med. Spent 2015, 58 (23), 9345-9353.

ESSENCE OF THE INVENTION

The invention relates to the compound of Formulas (I) and (Ia) 2 or about

K vytoyikh in 2 zeu N train

M

(I) e2

She

From visa E M r -

M

(Ia) where p" and 0-2 are each independently M or CH;

B" is H, or (C1-C6)alkyl optionally substituted with one or two substituents, each independently selected from fluorine and (C3-C6)cycloalkyl;

IN? is H or fluorine; vo o, Zh s M se; Z x x M x

M. U

VZ is shk; "ro" or "7 V.

B" is H, cyano or (C:1-C4)alkyl, optionally substituted with one or two substituents, each independently selected from -OH and -5(O)286;

Vo is H or -OH; and

Be is (C1-Ca)alkyl; or a pharmaceutically acceptable salt thereof.

The invention also relates to a crystal containing a compound having the structure:

Not yet

M or its pharmaceutically acceptable salt.

The invention also relates to pharmaceutical compositions containing a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt of said compound, which is present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

In addition, the invention relates to pharmaceutical compositions that contain a compound (I) or (Ia) or a pharmaceutically acceptable salt of said compound, which is present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient and which additionally contains at least one additional pharmaceutical agent , selected from the group consisting of an anti-inflammatory agent, an anti-diabetic agent, and a cholesterol/lipid modulating agent.

In another embodiment, the method of the invention is for the treatment of hyperlipidemia, diabetes mellitus type I, diabetes mellitus type II, idiopathic diabetes mellitus type I (type II), latent autoimmune diabetes in adults (GABA), early onset type 2 diabetes (EBD) , atypical diabetes with onset at a young age (AMD), adult-onset diabetes in the young (AMD), associated with wasting diabetes, gestational diabetes, ischemic heart disease, ischemic stroke, restenosis after vascular plastic surgery, peripheral vascular disease, dyslipidemia , postprandial lipemia, states of impaired tolerance to

From glucose (IT), states of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis , chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, erectile dysfunction, disorders skin and connective tissue, foot ulcers and non-specific ulcerative colitis, endothelial dysfunction and violation of vascular compliance, hyper aro B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome, nonalcoholic steatohepatitis (MA5N), or nonalcoholic fatty liver disease (NAFLD) in humans.

In another embodiment, the method reduces portal hypertension, hepatic protein synthesis, hyperbilirubinemia, or encephalopathy.

The invention also relates to a method of treatment for reducing at least one parameter of the severity of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis according to the evaluation system, reducing the level of serum markers of non-alcoholic steatohepatitis activity, reducing the activity of non-alcoholic steatohepatitis disease or reducing the medical consequences of non-alcoholic steatohepatitis in humans, which includes the stage of administration to humans. in need of such reduction, diabetes mellitus, which comprises administering an effective amount of a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt of said compound or a pharmaceutically acceptable salt of said compound to a patient in need thereof.

The invention also relates to a method of treating fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma, a metabolic or metabolically related disease, condition or disorder in humans. , which includes the step of administering to a person in need of such treatment, which includes the step of administering to the patient a therapeutically effective amount of a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt of said compound.

The invention also relates to a method of treating fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis, or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma, a metabolic or metabolically related disease, condition or disorder in humans , which includes the step of administering to a person in need of such treatment, which includes the step of administering to a patient in need of such treatment, a therapeutically effective amount of two separate pharmaceutical compositions, which include () a first composition containing a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt of the specified compound, present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient; and (i) a second composition containing at least one additional pharmaceutical agent selected from the group consisting of an anti-inflammatory agent, an anti-diabetic agent, and a cholesterol/lipid-modulating agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.

It should be understood that both the above general description and the following detailed description are illustrative and explanatory only, and are not restrictive of the invention as claimed.

BRIEF DESCRIPTION DRAWING

In Fig. 1 presents a characteristic powder X-ray diffractogram, which

20 shows crystalline Form 1 from Example 1 (Vertical axis: Intensity (CRP);

Horizontal axis: Two theta (degrees)).

In Fig. 2 shows a characteristic powder X-ray diffraction pattern showing crystalline form 2 from example 1 (Vertical axis: Intensity (CRB);

Horizontal axis: Two theta (degrees)).

Fig. C and 4 are a summary of the effects of oral administration from Example 1 on plasma and liver triglyceride levels in Sprague-Dawley rats fed a Western diet, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The invention can be understood more easily by reference to the following detailed description of illustrative embodiments of the invention and examples included herein.

It should be understood that the present invention is not limited to certain methods of synthesis, which may vary routinely. In addition, it should be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting. In this description and in the clauses that follow, reference will be made to a number of terms that have the following meanings:

As used herein, in the description, the singular may mean one or more.

As used herein, in clauses) of the claims, when used in conjunction with the expression "comprising", the singular term may mean one or more than one. As used herein, "Other" may mean at least a second or more.

The term "about" refers to the corresponding term meaning approximately plus or minus 10 95 of the nominal value to which it refers, in one embodiment, plus or minus 5 95, in another embodiment, plus or minus 2 95. For the field of description, this level of approximation is acceptable as long as a specifically defined value does not require a narrower interval. "Compounds" as used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric, and other mixtures thereof. isomers, as well as the term "prodrug" refers to compounds that are precursors of the drug, which after administration, release the drug as a result of some chemical or physiological process (for example, the prodrug form under the influence of physiological pH or due to the action of an enzyme is transformed into the desired drug form).

Examples of prodrugs that, upon cleavage, release the corresponding free acid and such hydrolyzable residues of the compounds that form the esters of the invention include, but are not limited to, those having a carboxyl residue in which the free hydrogen is substituted with (Ci-Ca)alkyl, (C»-C7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl, which has from 4 to 9 carbon atoms, 1-methyl-1--(alkanoyloxy)ethyl, which has from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl, which has from C to b carbon atoms, 1-(Alkoxycarbonyloxy)ethyl, which has 4 to 7 carbon atoms, 1-methyl-1-(Alkoxycarbonyloxy)ethyl, which has 5 to 8 carbon atoms, M-(Alkoxycarbonyl)aminomethyl, which has from 3 to 9 carbon atoms, 1-(M- (Alkoxycarbonyl)amino)dethyl, which has from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-M, M- (C1-C6)alkylamino(C2-C3)alkyl (such as pD-dimethylaminoethyl), carbamoyl-(C1-C6)alkyl, M, M-di(C1i-C6)alkylcarbamoyl-(C1-C6)alkyl and piperidino- , pyrrolidino-ab o morpholino(Cg2-C3)alkyl. / h

As used herein, an arrow, " ", or a wavy line, "i / 7" denotes the point of attachment of a substituent to another group. "Alkyl" means a straight chain saturated hydrocarbon or a branched chain saturated hydrocarbon. Examples of such alkyl groups (provided that the definition of length is covered by the specific example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.

The term "aryl" means a carbocyclic aromatic system containing one, two or three rings, where such rings may be fused. If the rings are annulated, one of the rings must be fully unsaturated and the annulated ring(s) may be fully saturated, partially unsaturated, or fully unsaturated. The term "annealed" means that the second ring present (ie, attached or formed) has two adjacent atoms in common use (ie, shared) with the first ring. The term "annealed" is equivalent to the term "condensed". The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, benzo(Hb1N1,4oxazin-3(4H)-onyl, 2,3-dihydro-1H-indenyl, and 1,2,3,4 -tetrahydronaphthalenyl. "Cycloalkyl" refers to a non-aromatic ring that is fully hydrogenated, having one, two, or three rings, where such rings may be ringed, where ringed is as defined above. Cycloalkyl also includes bicyclic structures that may be bridged or spirocyclic in nature with each particular ring within the bicycle varying from 3 to 8 atoms.Examples of such carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "heteroaryl" means an aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from oxygen, nitrogen, and sulfur, and having one, two, or three rings, wherein such rings may be fused, wherein fused is defined above.

The term "heteroaryl" includes, but is not limited to, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridiazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-onyl, pyridazine-2(1H)-onyl, pyrimidine-2(1H)-onyl, pyrazin-2(1H)-onyl, imidazo(1,2-a|pyridinyl, pyrazolo|1,5-a|pyridinyl, 5,6 . ... |(1,2-5111,2,AIgriazolyl, 5,6,7,8-tetrahydro-1,2,4Igriazolo|1,5-a|pyridinyl, 4,5,6,7- tetrahydropyrazolo|1,5- α|Ipyridinyl, 4,5,6,7-tetrahydro-1H-indazolyl and 4,5,6,7-tetrahydro-2H-indazolyl.

It should be understood that if a carbocyclic or heterocyclic moiety can be bonded or otherwise attached to a specified substrate through various ring atoms without specifying a specific point of attachment, then all possible points are meant, namely through a carbon atom or, for example, a trivalent atom nitrogen For example, the term "pyridyl" means 2-, 3-, or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, etc. "Patient" refers to warm-blooded animals such as, for example, guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and humans. "Pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients contained in the preparation and/or the mammal to which it is administered.

As used herein, the terms "reaction-inert solvent" and "inert solvent" refer to a solvent or mixture thereof that does not interact with the starting materials, reactants, intermediates, or products in the sense of adversely affecting the yield of the desired product.

As used herein, the term "selectivity" or "selective" refers to the greater activity of a compound in a first study compared to the activity of the same compound in a second study. For example, in "intestinal selectivity" of compounds, the first study is to determine the half-life of the compound in the intestine and the second study is to determine the half-life of the compound in the liver. "Therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (ii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

The term "treating," "treating," or "treatment," as used herein, includes both preventive, i.e., prophylactic, and palliative, i.e., alleviating, mitigating, or slowing the progression of a patient's disease (or condition) or any tissue damage associated with the disease.

The compounds according to the invention may contain asymmetric or chiral centers, and thus exist in various stereoisomeric forms. Unless otherwise indicated, it is intended that all stereoisomeric forms of the compounds of the invention, as well as mixtures thereof, including racemic mixtures, constitute part of the invention. In addition, the invention covers all geometric and positional isomers. For example, if the compound of the invention contains a double bond or a fused ring, both cis- and trans-forms, as well as mixtures, are covered by the scope of the invention.

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SCLC), on a resin with an asymmetric stationary phase and with a mobile phase containing a hydrocarbon , typically heptane or hexane, which contains from 0 to 50 95 isopropanol, typically from 2 to 20 95, and from 0

From to 5965 alkylamine, typically 0.195 diethylamine (DEA) or isopropylamine. The concentration of the eluent gives an enriched mixture.

Diastereomeric mixtures can be separated into their individual diastereoisomers based on their physicochemical differences using methods well known to one skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be resolved by converting an enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary compound such as a chiral alcohol or Mosher acid chloride), separating the diastereomers, and converting (e.g., by hydrolysis) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated using HPLC with a choral column. Alternatively, specific stereoisomers can be synthesized using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one stereoisomer into another using an asymmetric transformation.

When the compounds of the invention have two or more stereogenic centers and the absolute or relative stereochemistry is given in the name, the designations K and 5 refer, respectively, to each stereogenic center in numerically increasing order (1, 2, 3, etc.) according to the usual ISRAS numbering schemes of each molecule. When the compounds of the invention have two or more stereogenic centers and the stereochemistry is not specified in the name or structure, it is to be understood that the name or structure covers all forms of the compound, including the racemic form.

The compounds of the present invention may contain olefinic double bonds. When such linkages are present, the compounds of the invention exist in both cis and trans configurations and as mixtures thereof.

The term "cis" refers to the orientation of the two substituents relative to each other and the plane of the ring (either both "up" or both "down"). Similarly, the term "trans" refers to the orientation of two substituents relative to each other and to the plane of the ring (the substituents are on opposite sides of the ring).

It is also possible that the intermediates and compounds of the invention may exist in various tautomeric forms, and all such forms are encompassed by the scope of the invention. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interchangeable due to a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions due to proton migration, such as ketoenol and imine-enamine isomerizations.

Valence tautomers involve interconversion due to the reorganization of some bound electrons.

Included within the scope of the claimed compounds according to the invention are all stereoisomers, geometric isomers and tautomeric forms of compounds of Formula (I), including compounds that exhibit more than one type of isomerism and mixtures of one or more of these types. Also included are acid addition or basic salts where the counterion is optically active, for example, O-lactate or I - lysine, or a racemate, for example, O -tartrate or b -arginine.

The invention relates to all pharmaceutically acceptable isotopically labeled compounds of Formula (1) in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number that differs from the atomic mass or mass number normally found in nature .

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, of carbon, such as "C, 19C, and "C, of chlorine, such as 35Cl, of fluorine, such as 18g, of iodine, such as 729|, 124 ) and 125I, nitrogen, such as "ZM and "M, oxygen, such as 720, 770 and 780, phosphorus, such as ЗР, and sulfur, such as 255.

Certain isotopically labeled compounds of Formula (I), such as those incorporating radioactive isotopes, are useful in studies of drug and/or substrate tissue distribution.

Radioactive isotopes of tritium, i.e., ZN, and carbon-14, i.e., C, are particularly useful for these purposes, given their ease of incorporation and available means of detection.

Substitution with heavier isotopes such as deuterium, e.g., 2H, offers some therapeutic advantages in terms of greater metabolic stability, e.g., increased half-life of ip mimo, or reduced dosage required, and may therefore be preferable in some cases.

Substitution with positron-emitting isotopes such as "C, "9E, 150 and "ZM" can be useful in Positron Emission Tomography (PET) studies to determine receptor blocking by a substrate.

Isotopically labeled compounds of Formula (I) are generally prepared using conventional techniques,

Z are known to one skilled in the art or by techniques similar to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents instead of the unlabeled reagent used heretofore.

The compounds of the invention can be isolated and used directly, or whenever possible in the form of a pharmaceutically acceptable salt thereof. The term "salts" refers to inorganic and organic salts of a compound of the invention. These salts may be obtained during the final isolation and purification of the compound, or by separate treatment of the compound with an acceptable organic or inorganic acid or base and isolation of the resulting salt.

The acids used to prepare pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds according to the invention are acids that form non-toxic acid addition salts (ie, salts that contain pharmacologically acceptable anions such as hydrochloride, hydrobromide, hydroiodide, nitrate , sulfate, bisulfate, phosphate, hydrophosphate, acetate, lactate, citrate, hydrocitrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, hexafluorophosphate , benzenesulfonate, tosylate, formate, trifluoroacetate, oxalate, besylate, palmitate, pamoate, malonate, stearate, laurate, malate, borate, p-toluenesulfonate, and pamoate (ie, 1,1-methylene-bis-(2-hydroxy-3- naphthoate)).

The invention also relates to base-addition salts of compounds according to the invention. Chemical agents that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention, which are acidic in nature, are bases that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, salts derived from pharmacologically acceptable cations, such as alkali metal cations (e.g., lithium, potassium, and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium, or water-soluble salts. addition of an amine such as M-methylglucamine-(meglumine), tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines. See, for example, Vegod, ei ai. U. Riagt. from 66, 1-19 (1977).

Certain compounds of the invention may exist in more than one crystalline form (generally referred to as "polymorphs"). Polymorphs can be obtained by crystallization under different conditions, for example, using different solvents or different mixtures of solvents for recrystallization; crystallization at different temperatures; and/or different cooling regimes that vary from very fast to very slow cooling during crystallization.

Polymorphs can also be obtained by heating or melting the compound according to the invention, after which it is gradually or rapidly cooled. The presence of polymorphs can be determined using solid-state NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray imaging, or other techniques. 0;

In u x ri

In one embodiment, the short circuit is . in another embodiment, the short circuit is .

In a further embodiment, KE is methyl.

In yet another embodiment, K- is H, -CHNOOH, or cyano.

In another embodiment, the compound is: (5)-2-(5-(3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)/pyrimidine -5-carboxamide;

M-(2-cyanopropan-2-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)/pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-(hydroxymethyl)tetrahydrofuran-3-yl)/pyrimidine-5-carboxamide; (8)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-(hydroxymethyl)tetrahydrofuran-3-yl)/pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(2-methyl-1-(methylsulfonyl)propan-2-yl)/pyrimidin-5-carboxamide; (5)-2-(5-(3-(2-fluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)/pyrimidin-5-carboxamide; 3-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-

Co) triazine-6-carboxamide;

M-(1,3-dihydroxy-2-methylpropan-2-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)/pyrimidin-5-carboxamide; (5)-3-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-1,2,4-triazin-6-carboxamide;

M-(1,1-dioxidotetrahydrothiophen-3-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)/pyrimidine-5-carboxamide; (8)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide; or (5)2-(5-((3-ethoxypyrazin-2-yl)/oxy)pyridin-3-yl)-M-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-

B-carboxamide; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is: (8!)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl) /pyrimidine-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide; or (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)upyrimidine-5-carboxamide, or their a pharmaceutically acceptable salt.

In the following embodiment, the compound has the structure:

and: (c)

M gu ro: em ya M t:

Not yet

M or its pharmaceutically acceptable salt.

In a further embodiment, the compound of Formula (I) or (Ia) or a salt of the compound is present in the pharmaceutical composition in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient.

In a further embodiment, the composition additionally includes at least one additional pharmaceutical agent selected from the group consisting of an anti-inflammatory agent, an anti-diabetic agent, and a cholesterol/lipid modulating agent.

In one embodiment, the method of treating diabetes comprises administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt of said compound to a patient in need thereof.

In another embodiment, the method of treating a metabolic or metabolic-related disease, condition or disorder includes the step of administering to a patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt of said compound.

In another embodiment, the method of treating a condition selected from the group consisting of hyperlipidemia, diabetes | type, type II diabetes, idiopathic type I diabetes (type IB), latent autoimmune diabetes in adults (I ABA), early-onset type 2 diabetes (EOB)), atypical diabetes with onset at a young age (UAO), adult-onset diabetes of age in the young (MOOU), associated with wasting diabetes, gestational diabetes, ischemic heart disease, ischemic stroke, restenosis after plastic vascular surgery, peripheral vascular disease, intermittent claudication, myocardial infarction (eg, necrosis and apoptosis), dyslipidemia, postprandial lipemia, states of impaired glucose tolerance (IST), states of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, X syndrome, premenstrual syndrome, coronary vessels of the heart, angina pectoris, thrombosis,

From atherosclerosis, myocardial infarction, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, insulin resistance, impaired glucose metabolism, states of impaired glucose tolerance, states of impaired fasting plasma glucose, obesity, erectile dysfunction, disorders skin and connective tissue, foot ulcers and non-specific ulcerative colitis, endothelial dysfunction and violation of vascular compliance, hyper aro B lipoproteinemia, diseases

Alzheimer's, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and irritable bowel syndrome, non-alcoholic steatohepatitis (NAS), non-alcoholic fatty liver disease (NAFLD), comprises administering an effective amount of a compound according to the invention or a pharmaceutically acceptable salt of said compound .

In a further embodiment, the method of treating a metabolic or metabolic-related disease, condition or disorder includes the step of administering to a patient in need of such treatment two separate pharmaceutical compositions comprising () a first composition according to the invention; and (i) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent and an anti-diabetic agent, and at least one pharmaceutically acceptable excipient.

In yet another embodiment, the method according to the invention is carried out in such a way that the specified first composition and the specified second composition are introduced simultaneously.

In yet another embodiment, the method according to the invention is carried out in such a way that the first composition and said second composition are introduced sequentially and in any order.

In one embodiment, when two compositions are administered, the first composition and the second composition are administered simultaneously. In another embodiment, the first composition and the second composition are administered sequentially and in any order.

Compounds of the invention can be synthesized using methods of synthesis that include methods similar to those well known in the chemical industry, in particular, in light of the description given in this document. The starting materials are usually available from commercial sources, such as Algispi SpetisaI!e (Mim/"aiKeee, M/) or are readily prepared using methods well known to those skilled in the art (e.g., obtained by the methods generally described in G. R. Rieseg apa Magu Riezeg, Keadepiv Ttog Ogdapis Zupipeviv, m. 1-19,

MMPeu, Mem Hogk (1967-1999 ea.), or Veiivieip5 Napdrisi deg ogdapizspep Spetiye, 4, Aitsii. Hey.

Zrgipde!-Mepad, Vegpipe, including add-ons (also available via online database

Veiiiviviip)). Most of the compounds used herein are related to or are derivatives of compounds for which there is significant scientific interest and commercial need and, accordingly, most of such compounds are commercially available, or described in the literature, or are easily prepared from other commonly available substances. according to the methods described in the literature.

For purposes of illustration, the reaction schemes below represent potential routes for the synthesis of the compounds of the invention, also as key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. One skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. Although specific starting materials and reagents are discussed below, they can be easily substituted with other starting materials and reagents in order to obtain different derivatives and/or change the reaction conditions. In addition, most of the compounds obtained by the methods described below can be further modified in light of the description using conventional chemical approaches well known to one skilled in the art.

When preparing compounds of Formula I, it should be noted that some methods of preparation acceptable for the preparation of compounds described herein may require protection of remote functional groups (eg, primary amine, secondary amine, carboxyl in precursor compounds of Formula I). The need for such protection will vary depending on the nature of the remote functional group and the conditions of implementation of the methods of obtaining. The need for such protection can easily be determined by a skilled person in the field. The use of such methods of protection/removal of protection is also within the scope of the knowledge of a skilled specialist in this field. For an overview of guard groups and their use, see

TM. Sgeyepe, Rgoyesiime Stoyrz ip Ogdapis Zupipeviv, dopp U/eu in 5opv, Mem HogKk, 1991.

For example, certain compounds contain primary amine or carboxyl functional groups that can interfere with reactions elsewhere in the molecule if left unprotected.

Accordingly, such functional groups may be protected by an acceptable protecting group, which may be removed at a later stage. Acceptable amino and carboxy protecting groups include those commonly used in peptide synthesis (such as M-tert-butoxycarbonyl (Bos), benzyloxycarbonyl (Cp2), and 9-fluorenylmethyleneoxycarbonyl (Ethos) for amines and lower alkyl or benzyl esters for carboxy groups), which are usually not chemically reactive under the described reaction conditions and, as a rule, can be removed without chemically changing another functional group in the compounds of the Formula

She and A.

The reaction schemes described below are intended to provide a general description of the methodology for preparing the compounds of the invention. Some of the compounds of the invention contain a single chiral center. In the following schemes, general methods of obtaining compounds in either racemic or enantiomerically enriched form are shown. It should be apparent to one skilled in the art that all synthetic transformations can be carried out in the same manner when the materials are enantioenriched or racemic. In addition, separation of the desired optically active material may occur at any desired time using well-known methods such as those described herein and in the chemical literature.

WHEREAS, in Reaction Schemes I and II, the variables 0", 02, B", B, and BZ are as described in the Summary of the Invention section, unless otherwise noted. Variable B is methyl or ethyl. Reaction Scheme I discloses general techniques that can be used to prepare compounds of the invention having Formulas I.

Scheme of reaction I veto is what a sho vena with o", their neo 7 g vehstvo i seder podproliv uter mer on shenin y Fk nie sia ml schi ey h what Y i Her - |Й What M

Mono aboi en VE diea i onm m do she ' Sh yi ih o. what KN E. m -x se v sly, m EE Z i te i i Y g bu zhk what

Шк Ш Х и Хов, SMT, VYreЮ of en kl hm y we ONY ho B. Z, va Ve sh yh sche

Same SN va SYA Me t te y

Not owls whose | I am not this in Y not m HU hi VO Y in evAUOT and with pen ge minu" th

M PYh M ky

Compounds of Formula (I) can be synthesized starting from appropriate intermediates by methods described in the literature, such as: ). Honey. Spet., 2007, 50, 2990-3003; Mopaibvy Spet, 2012, 143, 1575-1592; 3. Med. Snet., 2011, 54, 6342-6363; Oh Rgos. Waves. YuOyem 2014, 18, 1145-1152; Apdem/. Spent Yippee Ed. 2011, 50, 9943; 9). At. Spent wasps 2005, 127, 8146; 9. Wow. Spent 2008, 73, 284; Oh9. Gene. 2002, 4, 973; Oh9. Gen., 2011, 13, 1840-1843; Goal! Saiaulei Stgo55-

Soiriipd Keasibp5 and Moge, Umieu-MSN, M/vippeit, Septapu, 2014, 3, 995; Arriisaiope oi

Tgapjiiop Mega! Saiauzi5 ip Ogyd Oibzsomegu and OemeIyuortepi, Chopp UmMieu 5 Zop5, Ips., NobokKep,

Mem Uegweeu, OBA, 2012, 3, 97. Intermediates (Ta) and (15) are commercially available and/or can be prepared by methods known to one skilled in the art.

For example, intermediates (Ta) and (15) can be synthesized by methods described in the literature, such as: May Spent 2000, 43, 3995; Wow9. Rgos. Ke5. JuOem 2010, 14, 936. Intermediates (2a) and (260) are commercially available or described in the literature and can be prepared by methods known to one skilled in the art, including those described below (Reaction Scheme I).

Intermediate compound (Za) can be obtained from intermediate compounds (Ta) and (2a) by a coupling reaction mediated by a transition metal. One of these halides (1a) or (2a) can be converted into an organometallic reagent, such as a boronic acid, zincate, stannane, or Grignard derivative, using methods well known to one skilled in the art.

The resulting organometallic reagent can then react with another halide intermediate in a transition metal-catalyzed cross-coupling reaction. Preferably, intermediate (2a) is converted to zincate and coupled to intermediate (1a) using a palladium or nickel catalyst in a reaction inert solvent such as toluene, 1,2-dimethoxyethane, dioxane, DMSO, DMF, or THF in the presence an acceptable ligand, and a base, such as sodium, potassium, or lithium tert-butoxide, or cesium carbonate, at a temperature from 10 "C to 130 "C according to the methods described in the literature, such as: U. Med. Spet., 2007, 50, 2990-3003; Mopaibyi Speth, 2012, 143, 1575-1592; IN.

May Spet., 2011, 54, 6342-6363; Oh Rgos. Be5. YuOyem 2014, 18, 1145-1152 or by other methods known to a skilled person in the art.

ZO Intermediate compound (4) can be obtained from the ester (Za) by a hydrolysis reaction under conditions well known to a person skilled in the art. Preferably, the intermediate compound (Za, K - methyl or ethyl) is treated with an aqueous base, such as sodium hydroxide, lithium hydroxide or potassium hydroxide, in an acceptable solvent or solvent mixture consisting of water, methanol and/or THF, at a temperature from 20 "C to 60 "C.

Compounds of Formula (I) can be prepared from acid (4) and amine (5) under amide preparation conditions well known to those skilled in the art, using coupling reagents such as propanephosphonic anhydride (TP), 1,1"-carbonyldiimidazole (СО), benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate (BOR), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methanaminium hexafluorophosphate (NATU), oxalyl chloride, O -benzotriazol-1-yl-M, M,M",M'-tetramethyluronium hexafluorophosphate (NVTU), 2-chloro-1,3-dimethylimidazolinium chloride (OMS), M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide ( EOSI) or 1-hydroxybenzotriazole (HBT) in an inert reaction solvent such as acetonitrile, dichloromethane (DCM), DMF, DMSO, or THF in the presence of a base such as triethylamine, M-methylmorpholine, or M,M-diisopropylethylamine at a temperature from 10 C to 90 "C, preferably from 20 "C to 65 C.

Alternatively, compounds of Formula (I) can be obtained by a two-step process from intermediate compound (15) and amine (5) by an amide coupling reaction to obtain intermediate compound (1c), followed by a metal-mediated coupling reaction with an aryl halide (2a). Preferably, intermediate compound (1c) is obtained from acid chloride (16, U-CI) and amine (5) in the presence of a base such as triethylamine or M,M-diisopropylethylamine in an inert reaction solvent such as dichloromethane at a temperature of - 20 "C to 30 "C, mostly from -

C to 0 "C. Alternatively, intermediate (1c) can be prepared from acid (16, U-OH) and amine (5) in the presence of a condensing reagent to form an amide, such as propanephosphonic anhydride (TP), 1, 1"-carbonyldiimidazole (CO), benzotriazol-1-yloxytridimethylamino)phosphonium hexafluorophosphate (BOR), 2-(1H-7-azabenzotriazol-1-yl)-20 1,1,3,3-tetramethyluronium hexafluorophosphatemethanaminium (NATO) , O-benzotriazol-1-yl-M,

M,M",M'-tetramethyluronium hexafluorophosphate (HVT), 2-chloro-1,3-dimethylimidazolinium chloride (OMS), M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide (EOSI) or 1-hydroxybenzotriazole (HVT) in an inert reaction solvent such as acetonitrile, dichloromethane, DMF, DMSO or THF in the presence of a base such as triethylamine, M-methylmorpholine or M,M-diisopropylethylamine at a temperature of from 10 "C to 90 "C. Compounds of Formula (I) can then be prepared from halides (1c) and (2a) by a transition metal-mediated coupling reaction. One of such halides (1c) or (2a) can be converted to an organometallic reagent such as a boronic acid, zincate, stannane, or Grignard derivative , using methods well known to those skilled in the art.The resulting organometallic reagent is then

Zo can interact with another halide intermediate in a transition metal-catalyzed cross-coupling reaction. Preferably, intermediate (2a) is converted to the zincate and coupled to intermediate (1c) using a palladium or nickel catalyst in a reaction inert solvent such as toluene, 1,2-dimethoxyethane, dioxane, DMSO, DMF, or THF, in presence of an acceptable ligand, and a base, such as sodium, potassium, or lithium tert-butoxide, or cesium carbonate, at a temperature from 10 "C to 130 "C according to the methods described in the literature, such as: U. May. Spet., 2007, 50, 2990-3003;

Mopaibzy Speth, 2012, 143, 1575-1592; 3. Med. Spet., 2011, 54, 6342-6363; Oho. Rgos. Nev. Oh yeah 2014, 18, 1145-1152, or by other methods known to a person skilled in the art.

As an option, the compounds of Formula (I) can be obtained from the intermediate compound (1c) by the threefold sequential introduction of addition of heteroaryl halide (20) followed by demethylation and addition of aryl halide (ba). The intermediate compound (35) can be obtained by a transition metal-mediated coupling reaction starting from halides (1c) and (265). One of these halides (1c) or (25) can be converted into an organometallic reagent such as boronic acid, zincate, stanna, or Grignard derivatives using methods well known to one skilled in the art. The resulting organometallic reagent can then react with another halide intermediate in a transition metal-catalyzed cross-coupling reaction.

Preferably, intermediate (25) is converted to zincate and coupled with intermediate (1c) using a palladium or nickel catalyst in a reaction inert solvent such as toluene, 1,2-dimethoxyethane, dioxane, DMSO, DMF, or TIF, in in the presence of an acceptable ligand, and a base, such as sodium, potassium, or lithium tert-butoxide, or cesium carbonate, at a temperature from 10 "C to 130 "C according to the methods described in the literature, such as: u). Honey. Spet., 2007, 50, 2990-3003; Mopaiz!y Spet, 2012, 143, 1575-1592; U. Med. Spet., 2011, 54, 6342-6363; Oh Rgos. Not. OEM 2014, 18, 1145-1152 or by other methods known to a skilled person in the art. Intermediate compound (Cc) can be obtained from intermediate compound (30) by demethylation using hydrohalic acids such as hydrobromic acid, bases such as sodium hydroxide or sodium alkoxide, boron tribromide, thiol, or by other methods known to a person skilled in the art. this industry. 60 For example, demethylation can be carried out by methods described in the literature, such as: Agsp Riapt Ne 2008, 31, 305-309; Teiapeadgop, 2005, 61, 7833-7863; Rgoiesiipa StoiMirv ip

Ogdapis Zupipeziv, add. UMPeu b Bopv, Ips., NoroKep, Mem dUegveu, OBA, 2007, 370-382. Compounds

Formulas (I) can then be prepared from a heteroaryl halide (ba) in a nucleophilic aromatic substitution reaction using an alcohol (Cc) in a reaction inert solvent such as dimethylsulfoxide (DMSO), M,M-dimethylformamide (DMF), acetonitrile, or tetrahydrofuran (THF), in the presence of an acceptable base, such as cesium carbonate, triethylamine (TEA) or M, M-diisopropylethylamine (OIREA) at a temperature from 20 "C to 160 "C. Preferably, intermediate compounds (ba) and (3c) react in DMSO, THF, or acetonitrile in the presence of triethylamine or M,M-diisopropylethylamine, at a temperature from 100 "C to 160 "C to obtain compounds of Formula (I) according to the methods described in the literature, such as: Teigapeagop 2005, 62 6000-6005, doitai oi Medisipa! Spetivigu, 2015, 58(7), 3036-3059.

Reaction scheme II shows the schematic synthesis of the intermediate compound (2a).

Scheme of the reaction of II and ! rya s «y WHAT PON EK NO ;

And B m che t | not me NA. and more food in -o ak savo vet, Vryu more and KI penny Nu kn vtoeyai dp ko

Intermediates (ba), (65), and (2c) are commercially available or described in the literature and can be prepared by methods known to one skilled in the art.

The intermediate compound (2a) can be synthesized by the reaction of nucleophilic aromatic substitution with a heteroaryl halide (ba) with hydroxypyridine (2c) in a reactive inert solvent such as dimethyl sulfoxide (DMSO), M, M-dimethylformamide (DMF), acetonitrile, M-methyl -2-pyrrolidinone (MMP), or tetrahydrofuran (THF), in the presence of an acceptable base, such as cesium carbonate, potassium carbonate, triethylamine (TEA) or M, M-diisopropylethylamine (OIREA) at a temperature from 20 "C to 160 "C . Preferably, intermediate compounds (ba) and (2c) interact in DMSO, MMP, or acetonitrile in the presence of triethylamine or M,M-diisopropylethylamine, at a temperature from 100 "C to 160 "C to obtain intermediate compound (2a), using methods, described in the literature, such as: Teigapedgop 2005, 62 6000-6005, doitai! oh Medisippa! Spetivigu, 2015, 58(7), 3036-3059. Alternatively, the intermediate compound (2a) can be synthesized using a transition metal that promotes the formation of an ether between the hydroxy-aromatic coupling member (26) and the aromatic halide (ba) using methods such as those described in: Uvziv, 2011, 353, 3403-

From 3414; Spetivigu - A Eptoreap mahttai, 2015, 21, 8727-8732; Zupivei 2012, 23, 101; 9. Oh. Spent 2009, 74, 7187; Oh9. Gene. 2007, 9, 643; Apdem Spent Ipii. Ed. 2011, 50, 9943; U. At. Spent 5 o0bs. 2005, 127, 8146; 9. Oh. Snet 2008, 73, 284; Oh And hey. 2002, 4, 973. The corresponding starting materials (ba) and (2c) can be treated with a metal salt such as cuprous(I) chloride, cuprous(I) bromide, or cuprous(I) iodide, and a ligand such as 2,2 ,6,6-tetramethylheptane-3,5-dione, 1,10-phenanthroline, or other acceptable ligand, in a reaction inert solvent such as toluene, DMSO, or DMF, in the presence of a base such as potassium carbonate, cesium carbonate, or potassium phosphate, at a temperature from 80 "C to 120 "C. Preferably, the corresponding starting materials (ba) and (2c) are treated with cuprum(I) chloride and 2,2,6,6-tetramethylheptane-3,5-dione, in toluene, in the presence of cesium carbonate, at a temperature from 100 "C to 120 "S.

Alternatively, the intermediate compound (2a) can be obtained from a two-stage sequential introduction with the formation of M-oxide (bs) followed by the addition of hydroxylpyridine (2c). The m-oxide (bs) can be derived from oxidizing agents such as m-chloroperoxybenzoic acid, hydrogen peroxide, potassium permanganate, or other oxidizing agents known to one skilled in the art in a reactive inert solvent such as dichloromethane, 1,2- dichloroethane or acetonitrile at a temperature from 0 "C to 25 "C. Preferably, the intermediate compound (65) reacts in dichloromethane with m-chloroperoxybenzoic acid at a temperature from 10 C to 25 "C to obtain the intermediate compound (bs). The intermediate compound (2a) can be obtained from the intermediate compound (bs) and the intermediate compound ( 2c) in the presence of bromotripyrrolidinophosphonium hexafluorophosphate (RUBhoOR) in a reactive inert solvent such as tetrahydrofuran, dichloromethane, or dioxane at a temperature from 10 "C to 25 "C. Preferably, the intermediate compound (bs) interacts with the intermediate compound (2c) in the presence of bromotripyrrolidinophosphonium of hexafluorophosphate in tetrahydrofuran at a temperature from 10 "C to 25 "C, as described in

Oh And ey., 2011, 13, 1840-1843.

COMBINED MEANS

The compounds of the invention may be administered alone or in combination with one or more additional therapeutic agents. "Administered in combination" or "combination therapy" means that the mammal being treated is simultaneously administered a compound of the invention and one or more additional therapeutic agents. When administered in combination, each component may be administered at the same time or sequentially in any order at different time points. Thus, each component can be administered separately, but close enough in time to provide the desired therapeutic effect. Thus, the methods of prevention and treatment described herein include the use of combined agents.

The combined agents are administered to the mammal in a therapeutically effective amount. "Therapeutically effective amount" means that amount of a compound of the invention which, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective in the treatment of a desired disease/condition, e.g., obesity, diabetes, and cardiovascular conditions, such as hypotensive agents, and ischemic heart disease

Examples of acceptable antidiabetic agents include (eg, insulins, metformin,

From ORRIM inhibitors, CI P-1 agonists, analogs and mimetics, 5 T1 and 5 TSI inhibitors 12). Acceptable antidiabetic agents include an acetyl-CoA carboxylase (ACC) inhibitor such as those described in M/O 2009144554, MO 2003072197, MO 2009144555 and MO 2008065508, a diacylglycerol O-acyltransferase 1 (DAC-1) inhibitor such as those , which are described in UUO 09016462 or MO 2010086820, A07687 or I СО908, monoacylglycerol O-acyltransferase inhibitor, phosphodiesterase (POE)-10 inhibitor, AMRK activator, sulfonylureas (for example, acetohexamide, chlorpropamide, diabinez, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, glichidone, glisolamide, tolazamide, and tolbutamide), meglitinide, α-amylose inhibitor (eg, tendamistat, trestatin, and A-3688), α-glucoside hydrolase inhibitor (eg, acarbose), α-glucosidase inhibitor (eg, adiposin, camiglibose, emiglitate, miglitol, voglibose, pradymicin-O ota salbostatin), PRACu agonist (eg, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pilglitazone, and rosiglitazone), PRAC a/u agonist (eg,

SI X-0940, (MU-1536, СМуУ-1929, СМуУ-2433, KAR-297, I -796449, 18-90, MK-0767 and 58-219994), biguanide (for example, metformin), modulator of glucagon-like peptide 1 (CI P-1), such as agonist (eg, exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Vueyaf), albiglutide, lixisenatide, dulaglutide, semaglutide, MIC-9924, TTR-054, protein tyrosine phosphatase inhibitor- 1B (PTR-18) (for example, trodusquemin, hirtiozal extract and compounds described in 2Napod, 5., ei aiY.,, Ogyd Oivsomegu Todau, 12(9/10), 373-381 (2007)), 5IVT-1 activator (for example, resveratrol, a5zkK2245840 or a5zK184072), a dipeptidyl peptidase IM inhibitor (OPP-IM) (for example, those described in M/O 2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretion stimulator, oxidation inhibitor fatty acid, A2 antagonist, inhibitor of c-hsp amino-terminal kinases (MK), glucokinase activators (SiKa), such as those described in MO 2010103437, UMO 2010103438, MO 2010013161, MO 2007122482, TTR-399, TTR-355, TTR-547, A20O1656, AVNU403, MK-0599, TAK-329, AYO5658 or (aKkM-001, insulin, insulin mimetic, glycogen phosphorylase inhibitor (eg, 45K1362885), MPAS2 receptor agonist , inhibitors 5 12 such as those described in

E.S. Snao her a. Maishte Nemiezhshe YuOhyd Oivsomegu 9, 551-559 (July 2010), including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (052452), Epidiyohip, ABR-1941, TNA1474, T5-071, I5I5388626 and I X4211, as well as those described in MO 2010023594, a glucagon receptor modulator such as those described in Oetopa, O.E. her AI Appia! Nerogi5 60 ip Medisipa! Spetivigu 2008, 43, 119-137, СРА119 modulators, partial agonists, such as those described in UMO 2010140092, MO 2010128425, MO 2010128414, MO 2010106457, addendum, V.M. evyi ai ip Meadisipai Spetivigu 2009, 44, 149-170 (for example, MVH-2982, p5K1292263, АРО597 and

RBOM821), derivatives or analogues of ЕСЕ21, such as those described in Kpagpiopecom, A. ейі аі. her aiI., Sitepi

Oripiop ip Ipmeviidaiopa! Ogydbe 2009, 10(4)359-364, TOV5 receptor modulators (also called SRVAVIs), partial agonists such as those described in popa, M., Sitepi Torisv ip

Meadisipa! Spetivig, 2010, 10(4), 386-396 and BMI777, CPA40O agonists such as those described in

Meadipa, 9US, Appia! Verogov ip Meadisipai Spetivigu, 2008, 43, 75-85, including but not limited to TAK-875, YARA120 modulators, partial agonists, high affinity nicotinic acid receptor activators (NM74A), and 5SCCI 11 inhibitors such as P5K1614235.

The following illustrative list of antidiabetic agents that can be combined with the compounds of the invention can be found, for example, on page 28, line 35 - page 30, line 19 of MO 2011005611. Preferred antidiabetic agents are metformin and OPR-IM inhibitors (eg, sitagliptin , vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other antidiabetic agents may include carnitine palmitoyltransferase enzyme inhibitors or modulators, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TOVS2 inhibitors,

SSV2 and/or SSV5, inhibitors of PKS isoforms (for example, РКСа, РКСВДВ, РКСУ), fatty acid synthetase inhibitors, serine palmitoyltransferase inhibitors, CPA81 modulators, RAZ,

CPA43, CPA41, CPA105, Km1,3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptors (eg, 55181, 55182, 55183, and 55185), RONK?2 or RONKA inhibitors or modulators, MARAKA inhibitors, HER family modulators 1, including II beta, AChNalfa modulators. In addition, acceptable antidiabetic agents include the mechanisms listed by Sagripo, RA, Ssoodm/p, V. Ehrep Orip. TNeg. Rai, 2010, 20(12), 1627-51.

Acceptable anti-obesity agents include 11β-hydroxysteroid dehydrogenase-1 inhibitors (118-H5O type 1), stearoyl-CoOA desaturase inhibitor (5C00-1), MCE-4 agonists, cholecystokinin-A (SSK-A) agonists, reuptake inhibitors monoamines (such as sibutramine), sympathomimetic agents, Bz adrenergic agonists, dopamine agonists (such as bromocriptine), melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin-concentrating hormone antagonists, leptin (OB protein), leptin analogs, leptin agonists, galanin antagonists,

Lipase inhibitors (such as tetrahydrolipstatin, i.e., orlistat), anorectic agents (such as bombesin agonist), neuropeptide-γ antagonists (eg, MRU MU5 antagonists), RUMUz-zv (including its analogs), thyromimetic agents, dehydroepiandrosterone or its analog , glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotropic factors (such as AhoKipe "M, available from Kedepegop Rpaptaseciis!5, Ips.,

Tatu, MU and Rgosieg 5 Satbie Sotrapu, Sipsippaiyi, ON), human agouti-related protein (ABP) inhibitors, ghrelin antagonists, histamine 3 antagonists or inverse agonists, neuromedin M agonists, MTP/AroB inhibitors (eg, gut-selective MTP inhibitors such as dirlotapide), opioid antagonist, orexin antagonist, combination of naltrexone with buproprion, etc.

Preferred antiobesity agents for use in combinations according to aspects of the invention include enteric-selective MTP inhibitors (e.g., dirlotapide, matratapide, and implitapide, 856918 (SAZ Mo. 403987) and CA5 Mo. 913541-47-6), SSKa agonists (e.g., M -benzyl-2-|4-(IN-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10p-tetraazabenzo(|e)azulen-b-yl |-M- isopropylacetamide described in PCT publication Mo MO 2005/116034 or 5 publication Me 2005- 0267100 At), 5HT2c agonists (eg, lorcaserin), MSKA agonist (eg, compounds described in 05 6,818,658), lipase inhibitor (eg, cetilistat), RUUz-zv (as used herein "RUUz-zee includes analogs such as pegylated RUUz-zv, for example those described in 5 publication 2006/0178501), opioid antagonists (eg, naltrexone), naltrexone combination with buproprion, oleoyl-estrone (SAB Mo. 180003-17-2), binepitide (TM30338), pramlintide (ZuptiipF), tesofensin (M52330), leptin, liraglutide, bromocriptine, orlistat, exena tid (VuetsafF), AOB-9604 (SA Mo. 221231-10-3), phentermine and topiramate (trade name:

Ozvutia), and sibutramine. Preferably, the compounds of the invention and combination therapeutics are administered in conjunction with exercise and an appropriate diet.

The compounds of the invention can be used in combination with cholesterol-modulating agents (including cholesterol-lowering agents), such as a lipase inhibitor, an inhibitor of NMAa-CoA reductase, an inhibitor of NMAa-CoA synthase, an inhibitor of NMAa-CoA reductase gene expression, an inhibitor of NMAa-CoA gene expression CoA synthase, MTP/Apo B secretion inhibitor, CETP inhibitor, bile acid absorption inhibitor, cholesterol absorption inhibitor, cholesterol synthesis inhibitor, squalene synthetase inhibitor, squalene epoxidase inhibitor, squalene cyclase inhibitor, combined squalene epoxidase/squalene cyclase inhibitor, fibrate, niacin, ion exchange resin, antioxidant, inhibitor

ASAT or bile acid excretory stimulant or an agent such as mipomersen.

Examples of acceptable cholesterol/lipid-lowering agents and lipid-modifying therapeutics include: HMoO-CoA reductase inhibitors (eg, pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, MK-104 (also known as itavastatin, or nisvastatin, or nisbastatin) and 2720-4522 (also known as rosuvastatin, or atavastatin, or visastatin)); inhibitors of squalene synthetase; fibrates; substances that increase the excretion of fatty acids (such as Questran); ASAT inhibitors; MTP inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors; and cholesterol ester transport protein inhibitors. Other atherosclerotic agents including PO5KO modulators.

In another embodiment, a compound of Formula I can be co-administered with agents for the treatment of non-alcoholic steatohepatitis (NASH) and/or non-alcoholic fatty liver disease (NAFLD), such as orlistat, T2O and other insulin sensitizers, ECE21 analogs, metformin, omega ethyl esters -3-acid (for example, lovaza), fibrates, NMO CoA reductase inhibitors, ezetimbe, probucol, ursodeoxycholic acid, TOK5 agonists, EHE. agonists, vitamin E, betaine, pentoxifylline, SVI antagonists, carnitine, M-acetylcysteine, reduced glutathione, lorcaserin, combination of naltrexone with buproprion, 501 T2 inhibitors, phentermine, topiramate, incretin analogues (CI P and CIP) and angiotensin receptor blockers.

In another embodiment, the additional pharmaceutical agent is selected from the group consisting of cysteamine or a pharmaceutically acceptable salt thereof, cystamine or a pharmaceutically acceptable salt thereof, an antioxidant compound, lecithin, a vitamin B complex, bile salt preparations, cannabinoid receptor antagonists (CRI), inverse agonist of regulators of activity of the cannabinoid receptor-1 (SVI), regulators of activity of the peroxisome proliferator-activated receptor, benzothiazepine or benzothiepine compound, RNA antisense construct for inhibition of protein tyrosine phosphatase PTRVAISH, heteroatom-bound substituted piperidine and its derivative, azacyclopentane derivative capable of inhibiting stearoyl - alpha-delta-9 desaturase enzyme, an acylamide compound that has secretagogue or adiponectin-inducing activity, a quaternary ammonium compound, a reductase inhibitor HMI-CoA, p-acetylcysteine, an isoflavone compound, a macrolide

Ko) antibiotic, galectin inhibitor, antibody or any combination thereof.

Additional therapeutic agents include anticoagulant or coagulation inhibitors, antiplatelet agents or platelet aggregation inhibitors, thrombin inhibitors, thrombolytic or fibrinolytic agents, antiarrhythmic agents, hypotensive agents, calcium channel blockers (type I and type T), cardiac glycosides, diuretics, mineralocorticoid antagonists receptor, MO donors such as organo-nitrates, MO promoting agents such as phosphodiesterase inhibitors, cholesterol/lipid-lowering agents and lipid-modifying therapeutic agents, anti-diabetic agents, antidepressants, anti-inflammatory agents (steroidal and non-steroidal), osteoporosis agents, hormone replacement therapy agents, oral contraceptives, antiobesity agents, sedatives, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux agents, growth hormone and/or stimulators of growth hormone secretion, thyroid mimetics (including antago thyroid hormone receptor blocker), anti-infectives, antivirals, antibacterials and antifungals.

Agents used in intensive care units include, for example, dobutamine, dopamine, epinephrine, nitroglycerin, nitroprusside, and the like.

Combination agents useful in the treatment of vasculitis include, for example, azathioprine, cyclophosphamide, mycophenolate, motefil, rituximab, and the like.

In another embodiment, the invention provides a combination in which the second agent, at least one agent, is selected from a factor Xa inhibitor, an anticoagulant, an antiplatelet agent, a thrombin inhibitor, a thrombolytic agent, and a fibrinolytic agent. Examples of factor Xa inhibitors include apixaban and rivaroxaban. Examples of acceptable anticoagulants for use in combination with the compounds of the invention include heparins (eg, unfractionated and low molecular weight heparins such as enoxaparin and deltaparin).

In another preferred embodiment, the second agent is at least one agent selected from warfarin, dabigatran, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin, argatrobanase, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidrogel, tirofiban, eptifibatide, abciximab, melagatran,

disulfatohirudin, activator of tissue plasminogen, activator of modified tissue plasminogen, anistreplase, urokinase and treptokinase.

A preferred second agent is at least one antiplatelet agent. Particularly preferred antiplatelet agents are aspirin and clopidogrel.

The term antiplatelet agents (or platelet aggregation inhibitors), as used herein, refers to agents that inhibit platelet function, for example, by inhibiting platelet aggregation, adhesion, or secretory granulation. Agents include, but are not limited to, various known nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and pharmaceutically acceptable salts or prodrugs thereof. Among the NSAIDs5, aspirin (acetylsalicylic acid or ABA) and COX-2 inhibitors such as Celebrex are preferred. Other acceptable platelet aggregation inhibitors include PB/Pa antagonists (eg, tirofibrate, eptifibatide, and abciximab), thromboxane A2 receptor antagonists (eg, ifetroban), thromboxane A2 synthetase inhibitors, ROB-II inhibitors (eg, pletal, dipyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

The term antiplatelet agents (or platelet aggregation inhibitors) as used herein also includes antagonists of the AR (adenosine diphosphate) receptor, preferably antagonists of the purinergic receptors Rom: and Ro", where RoMi2 is even more predominant. Preferred RoMi2 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is even more preferred. Ticlopidine and clopidogrel are also preferred compounds as they are known to be mild on the gastrointestinal tract when administered.

The term thrombin inhibitors (or antithrombin agents) as used herein refers to thrombin serine protease inhibitors. Inhibition of thrombin disrupts various thrombin-mediated processes, such as thrombin-mediated platelet activation (ie, for example, platelet aggregation, and/or secretory granulation of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrate formation. A number of thrombin inhibitors are known to those skilled in the art, and these inhibitors can be used in

From a combination with these compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, dabigatran, heparins, hirudin, argatroban, and melagatran, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include derivatives of M-acetyl and peptide derivatives of boronic acid, such as C-terminal alpha-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and their corresponding isothiouronium analogs. The term hirudin, as used herein, includes acceptable derivatives or analogues of hirudin, which are referred to herein as chirulogs, such as disulfahirudin.

The term thrombolytic or fibrinolytic agents (or thrombolytics or fibrinolytics), as used herein, refers to agents that destroy blood clots (clots). Such agents include tissue plasminogen activator (natural or recombinant) and its modified forms, anistreplase, urokinase, streptokinase, tenesteplase (TMK), lanoteplase (pRA), factor Miia inhibitors, RAI-1 inhibitors (ie, inactivators of tissue plasminogen activator inhibitors), alpha2g-antiplasmin inhibitors and anisoylated streptokinase complex activator, including their pharmaceutically acceptable salts or prodrugs. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex as described, for example, in EP 028,489, the disclosure of which is incorporated herein by reference in its entirety. The term urokinase, as used herein, refers to both double- and single-chain urokinase, the latter also being referred to herein as prourokinase.

Examples of acceptable antiarrhythmic agents include: class ! (such as propafenone); class II agents (such as metoprolol, atenolol, carvadiol, and propranolol); class PI agents (such as sotalol, dofetilide, amiodarone, azimilide, and ibutilide); class MI agents (such as ditiazem and verapamil); openers of K" channels, such as Idsp inhibitors and Ikyg inhibitors (for example, compounds described in MUO01/40231).

The compounds of the invention may be used in combination with hypotensive agents and such hypotensive activity is readily determined by one skilled in the art according to standard studies (eg, blood pressure measurement). Examples of acceptable hypotensive agents include: alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (eg, diltiazem, verapamil, nifedipine, and 60 amlodipine); vasodilators (eg, hydralazine), diuretics (eg, chlorothiazide,

hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, benzthiazide, tricrinafen of ethacrynic acid, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone); renin inhibitors; ACE inhibitors (for example, captopril, zofenopril, fosinopril, enalapril, seranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); antagonists

AT-1 receptor (for example, losartan, irbesartan, valsartan); ET receptor antagonists (eg, sitaxsentan, atrsentan, and compounds described in US patents 5,612,359 and 6,043,265); dual antagonists of ET/AII (for example, compounds described in M/UO 00/013859); inhibitors of neuronal endopeptidase (MER); vasopepsidase inhibitors (dual MER-ACE inhibitors) (eg, hemopatrilat and nitrates). A typical antianginal agent is ivabradine.

Examples of acceptable calcium channel blockers (I-type or T-type) include diltiazem, verapamil, nifedipine and amlodipine, and mibefradil.

Examples of acceptable cardiac glycosides include digitalis and suabain.

In one embodiment, a compound of Formula | can be administered together with one or more diuretics. Examples of acceptable diuretics include (a) loop diuretics such as furosemide (such as I ABIX M), torsemide (such as OEMAOEX "M), bemetanide (such as VIMEX 7M), and ethacrynic acid (such as EOESKIM M); (BU) thiazide diuretics such as chlorothiazide (such as

RIOKISTM, EBIOKIH"M or NUOKOBISHMKII M), hydrochlorothiazide (such as MISCOLIOEE "M or

ORETISTM), benzthiazide, hydroflumethiazide (such as ZAGSHOKOM'M), bendroflumethiazide, methychlorothiazide, polythiazide, trichlormethiazide and indapamide (such as 0201 tm); (c) phthalimide diuretics such as chlorthalidone (such as NUSKOTOM'M) and metolazone (such such as 2AKOXOY UM M); (a) quinoline diuretics such as hinetazone; and (e) potassium-sparing diuretics such as triamterene (such as OMKEMISHM "M) and amiloride (such as MIVTAMOK M or MOBIMETIS M),

In another embodiment, the compound of Formula I can be administered together with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of Formula I or Ia may be co-administered with furosemide. In yet another embodiment, one or more compounds

Formulas I or Ia can be administered together with torsemide, which may optionally be a controlled or modified release form of torsemide.

In another embodiment, a compound of Formula I can be co-administered with a thiazide-type diuretic. In yet another embodiment, the thiazide-type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of Formula I or Ia may be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of Formula ! or Ia can be administered together with hydrochlorothiazide.

In another embodiment, one or more compounds of Formula I or IIIa may be co-administered with a phthalimide-type diuretic. In yet another embodiment, the phthalimide-type diuretic is chlorthalidone. Examples of acceptable mineralocorticoid receptor antagonists include spironolactone and eplerenone. Examples of acceptable phosphodiesterase inhibitors include: ROE PP inhibitors (such as cilostazol); and POE M inhibitors (such as sildenafil).

One skilled in the art will appreciate that the compounds of the present invention may also be used in conjunction with other cardiovascular or cerebrovascular treatments, including PCI, bypass surgery, drug-eluting stents, stem cell therapy, and medical devices such as pacemakers. , implantable defibrillators or cardiac resynchronization therapy.

The dosage of an additional pharmaceutical agent will generally depend on a number of factors, including the health of the subject being treated, the duration of treatment desired, the nature and type of concomitant treatment, if any, and the frequency of treatment and the nature of the desired effect. In general, the dosage range of the additional pharmaceutical agent is in the range of from about 0.001 mg to about 100 mg per kilogram of body weight of the individual per day, preferably from about 0.1 mg to about 10 mg per kilogram of body weight of the individual per day. However, some variation in the general dosage range may also be required depending on the age and weight of the subject being treated, the intended route of administration, the particular anti-obesity agent being administered, and the like. Determination of dosage ranges and optimal dosages for a particular patient are within the skill of one skilled in the art having the benefit of this disclosure.

According to the methods of treatment of the invention, a compound of the invention or a combination of a compound of the invention and at least one additional pharmaceutical agent (referred to herein as a "combination") is administered to a subject in need of such treatment,

mainly in the form of a pharmaceutical composition. In a combination aspect of the invention, a compound of the invention and at least one other pharmaceutical agent (eg, another anti-obesity agent) can be administered either alone or in a pharmaceutical composition containing both.

As a rule, the preferred such administration is oral.

When a combination of a compound of the invention and at least one other pharmaceutical agent is administered together, such administration may be sequential or simultaneous.

Simultaneous administration of drug combinations is usually preferred. For sequential administration, the compound of the invention and the additional pharmaceutical agent may be administered in any order. As a rule, the preferred such administration is oral. Particularly preferred such administration is oral and simultaneous administration. When a compound of the invention and an additional pharmaceutical agent are administered sequentially, each may be administered by the same or a different route.

According to the methods of the invention, the compound of the invention or combination is preferably administered in the form of a pharmaceutical composition. Accordingly, a compound of the invention or combination may be administered to a patient alone or in combination by any of the commonly accepted oral, rectal, transdermal, parenteral (e.g., intravenous, intramuscular, or subcutaneous), intracisternal, intravaginal, intraperitoneal, topical (e.g., powder, ointment, cream, spray, or lotion), buccal or nasal dosage form (eg, spray, drops, or inhalant).

The compounds of the invention or combinations may be administered alone, but will generally be administered in admixture with one or more acceptable pharmaceutical excipients, adjuvants, diluents or carriers known in the art and selected according to the intended route of administration and standard pharmaceutical practice. A compound of the invention or combination may be formulated to provide immediate-, delayed-, modified-, sustained-, pulsatile-, or controlled-release dosage forms depending on the desired route of administration and the specificity of the release profile to meet therapeutic needs.

A pharmaceutical composition contains a compound of the invention or combination in an amount typically in the range of about 1 95 to about 75 95, 80 95, 85 95, 90 95 or even 95 95

Co) (by weight) of the composition generally in the range of about 1 95, 2 95 or C 956 to about 50 95, 60 95 or 70 95, more often in the range of about 1 95, 2 95 or C 95 to less , than 50 95, for example, about 25 95, 30 95, or 35 95.

Methods of obtaining various pharmaceutical compositions with a specific amount of active compound are known to a skilled specialist in this field. For examples, see Netipdiop:

TNe Rgasiise oi Rpaptasu, Iirripsoiy UMPPatv apa UMiiKipo, Waiitoge Ma. 20.5, r.y unit 2000

Compositions suitable for parenteral injection generally include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of acceptable aqueous and non-aqueous carriers or diluents (including solvents and carriers) include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerin, etc.), acceptable mixtures thereof, triglycerides including vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. A preferred carrier is Midiuo!"M, caprylic/caproic acid ester with glycerol or propylene glycol (eg, Midiuo!"M 812, Midiuo!"M 829, Midiuo!"M 840), available from SOMOBEA Mivia Co., Stapioga, Mo. )IN. The required fluidity can be maintained, for example, by the use of an emulsifier such as lecithin, which maintains the required particle size in the case of dispersions, and by the use of surfactants.

These compositions for parenteral injection may also contain excipients such as preservatives, wetting agents, emulsifying and dispersing agents. To prevent contamination by microorganisms, the compositions may contain various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc.

It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc.

Prolonged absorption of injectable pharmaceutical compositions can be ensured by using agents capable of delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, gums, pastilles, pills, powders, and multiparticulate preparations (granules). In such solid dosage forms, the compound of the invention or combination is admixed with at least one inert excipient, diluent or carrier. Acceptable excipients, diluents, or carriers include materials such as sodium citrate or dicalcium phosphate and/or (a) one or more excipients (eg, microcrystalline cellulose (available as Amise!M from EMC Sogr.),

starches, lactose, sucrose, mannitol, silicic acid, xylitol, sorbitol, dextrose, calcium hydrogen phosphate, dextrin, alpha-cyclodextrin, beta-cyclodextrin, polyethylene glycol, medium-chain fatty acids, titanium oxide, magnesium oxide, aluminum oxide, etc.); (b) one or more binding agents (such as carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, gum arabic, ethylcellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, etc); (c) one or more humectants (eg, glycerin, etc.); (4) one or more leavening agents (such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some complex silicates, sodium carbonate, sodium lauryl sulfate, sodium starch glycolate (available as

Ekhriotar"M from Edulaga Mepayeei! So.), cross-linked polyvinylpyrrolidones, croscarmellose sodium

A-type (available as As-alii-501I"M), potassium polyacrylin (ono-exchange resin), etc.); (e) one or more retarders (e.g., paraffin, etc.); () one or more absorption accelerators (e.g., quaternary ammonium compounds, etc.); (du) one or more wetting agents (eg, cetyl alcohol, glycerol monostearate, etc.); (n) one or more adsorbents (eg, kaolin, bentonite, etc.); and/or (i) one or more lubricants (such as talc, calcium stearate, magnesium stearate, stearic acid, polyoxystearate, cetanol, talc, hydrogenated castor oil, sucrose and fatty acid esters, dimethylpolysiloxane, microcrystalline wax, yellow beeswax, white beeswax, solid polyethylene glycols , sodium lauryl sulfate, etc.) In the case of capsules and tablets, dosage forms may also contain buffering agents.

Solid compositions of this type can also be used as fillers for soft or hard gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc.

Solid dosage forms such as tablets, dragees, capsules and granules can be prepared with coatings and shells such as enteric coatings and other types well known in the art. They can also contain matting agents and can also be such a delayed release composition. compounds according to the invention and/or an additional pharmaceutical agent. Examples of implantable compositions that can be

Among those used are polymeric substances and waxes. The drug may also be in microencapsulated form, when appropriate, with one or more of the above excipients.

For tablets, the active agent will typically be less than 50 95 (by weight) of the drug, for example, less than about 10 95, such as 5 95 or 2.5 wt. 95. The bulk of the preparation consists of fillers, thinners, leavening agents, lubricants and, optionally, flavorings. The composition of these excipients is well known in the art.

Often, fillers/diluents will consist of a mixture of two or more of the following components: microcrystalline cellulose, mannitol, lactose (all types), starch, and dicalcium phosphate. Filler/diluent mixtures are typically less than 9895 of the formulation and preferably less than 95 95, such as 93.5 95. Preferred disintegrants include As-aili-501"M,

Echrioyar"M, starch and sodium lauryl sulfate. When present, the disintegrant will usually be less than 1095 of the preparation or less than 595, for example, about 3 95.

The preferred lubricant is magnesium stearate. When present, the lubricant will usually be less than 5 95 of the formulation or less than C 95, for example about 1 95.

Tablets can be made by standard tableting techniques such as direct compression or wet or dry granulation or melt granulation, melt cooling and extrusion. Tablet cores may be mono- or poly-layered and may be coated with an acceptable coating known in the art.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the invention or combination, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn kernel oil, olive oil, castor oil, sesame oil, etc.), Midiuoie"M (available from SOMOEA Mivia So ., Stapioga,

M.9.), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan or mixtures of these substances, etc.

In addition to inert diluents, the composition may also include excipients such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and (516) flavoring agents.

Oral liquid forms of the compounds of the invention or combinations include solutions in which the active compound is completely dissolved. Examples of solvents include all pharmaceutical solvents acceptable for oral use, particularly those in which the compounds of the invention exhibit good solubility, such as polyethylene glycol, polypropylene glycol, edible oils, and glyceryl and glyceride systems. Glyceryl and glyceride systems may include, for example, the following branded products (and corresponding generic products): Sarieh"M 355 ER (glyceryl tricaprylate/caprate, from AbBiyes, Soimtry5 OPIO) Sgodato!M sts/S (medium-chain triglyceride, from Stgod, Som /isk Naii, ShK) or iIargagasm ss (medium-chain triglycerides, from Saceios55e), Sariekh"M 500R. (glyceryl triacetate, i.e., triacetin, from Abies), Sarty!"M MOM (medium-chain mono- and diglycerides, from Abies),

Miduo!"M 812 (caprylic/capric triglyceride, from Sopaea, Stapioga M.9.), Miduo!"M 829 (caprylic/capric/succinic triglyceride, from Sopaea), Miduo!"M 840 (propylene glycol dicaprylate/dicaprate, from Sopaea), IGargai mm Mm1944s5 (oleoyl macrogol-b glycerides, from

Sayeiov5e), Reseo/"M (glyceryl monooleate, from Saceiovze) and Maizipe"M 35-1 (glyceryl monooleate, from satsegto55e). Of particular interest are medium-chain (approximately St-Sto) triglyceride oils.

These solvents often make up the majority of the composition, ie, greater than about 50 95, usually greater than about 80 956, such as about 95 95 or 9995. Also included with the solvents are adjuvants and additives, mainly as taste masking agents, to create a pleasant taste and flavor, are antioxidants, stabilizers, texture and viscosity modifiers, and solubilizers.

Suspensions, in addition to the compound of the invention or combination, may additionally contain carriers such as suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances, etc.

Compositions for rectal or vaginal administration preferably include suppositories which may be prepared by mixing a compound of the invention or combination with acceptable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at room temperature but liquid at body temperature. and, in addition, melts in the rectum or vagina, thereby releasing the active(s)

From components).

Dosage forms for topical administration of the compound of the invention or combinations include ointments, creams, lotions, powders and sprays. The drugs are mixed with a pharmaceutically acceptable excipient, diluent or carrier and any preservatives, buffers or propellants that may be necessary.

Most of these compounds are poorly soluble in water, eg less than about 1 µg/ml.

In addition, liquid compositions in solubilizing, non-aqueous solvents, such as the medium chain triglyceride oils discussed above, are the preferred dosage form for these compounds.

Solid amorphous dispersions, including dispersions formed by spray drying, are also the preferred dosage form for poorly soluble compounds of the invention. "Solid amorphous dispersion" means a solid material in which at least a portion of the poorly soluble compound is in amorphous form and is dispersed in a water-soluble polymer. "Amorphous" means that the poorly soluble compound is not crystalline. "Crystalline" means that the compound exhibits long-range order in three dimensions of at least 100 repeat units in each direction. Thus, the term amorphous includes not only a material that is not essentially ordered, but also a material that may have some small degree of order, but the order is in less than three directions and/or is only over short distances. Amorphous material can be characterized using known techniques such as powder X-ray diffraction (XPR), solid state NMR or thermal methods such as differential scanning calorimetry (DSC).

Preferably, at least a major part (ie, at least about 60 wt. 95) of the poorly soluble compound in the amorphous solid dispersion is amorphous. The compound may exist within the dispersion of the amorphous solid in relatively pure amorphous domains or regions, as a solid solution of the compound homogeneously distributed throughout the polymer, or in any combination of these states or those states in between. Preferably, the dispersion of the amorphous solid is essentially homogeneous, so that the amorphous compound is uniformly dispersed throughout the polymer. As used herein, "substantially homogeneous" means that the fraction of the compound present in relatively pure amorphous domains or regions within the dispersion of the amorphous solid is relatively small, on the order of less than 20 wt. 95, and preferably less than 10 wt. 95 of the total amount of the medicinal product.

Water-soluble polymers acceptable for use in amorphous solid dispersions must be inert in the sense that they do not react chemically with the poorly soluble compound in an undesirable manner, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pH (e.g., 1 -8). The polymer can be neutral or ionizable and must have a water solubility of at least 0.1 mg/ml, at least partially at a pH in the range of 1-8.

Water-soluble polymers suitable for use in the invention may be cellulosic or non-cellulosic. Polymers can be neutral or ionized in aqueous solution. Among them, ionizable polymers and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.

Examples of water-soluble polymers include hydroxypropyl methyl cellulose acetate succinate (HMCA), hydroxypropyl methyl cellulose (HMCO), hydroxypropyl methyl cellulose phthalate (HMCP), carboxymethyl ethyl cellulose (CME), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinylpyrrolidone (PMP), hydroxypropyl cellulose (HPC), methyl cellulose ( MS), block copolymers of ethylene oxide and propylene oxide (PEO/PPO, also known as poloxamers) and their mixtures. Particularly preferred polymers are NRMSABZ, NRMS, NRMSR, SMES, SAR, SAT, RUR, poloxamers and their mixtures.

The most preferred is NRMSAF5. See European patent application No. 0 901 786 A2, the description of which is incorporated herein by reference in its entirety.

Amorphous solid dispersions can be obtained according to any method of obtaining an amorphous solid dispersion that provides at least the main part (at least 60 95) of the poorly soluble compound in an amorphous state. Such methods include mechanical, thermal and solvent methods. Examples of mechanical methods are grinding and extrusion; melting processes include high temperature melting, modified solvent melting and melt cooling processes; and solvent methods include non-solvent deposition, spray coating and spray drying. See, for example, the following patents

USA, the descriptions of which are incorporated herein by reference: Mo 5,456,923 and 5,939,099, which describe the preparation of dispersions by extrusion; Mo. 5,340,591 and 4,673,564, which describe the preparation of dispersions by milling; and Mo. 5,707,646 and 4,894,235, which describe the preparation of dispersions by cooling the melt. In a preferred method, the amorphous solid dispersion is prepared by spray drying as described in

European patent application No. 0 901 786 A2. In this method, the compound and the polymer are dissolved in a solvent such as acetone or methanol, and the solvent is then quickly removed from the solution by spray drying, yielding a dispersion of an amorphous solid.

Amorphous solid dispersions can be prepared so that they contain up to about 99 wt. 95 compounds, for example, when 1 wt. 95.5 wt. 95, 10 wt. 95, 25 wt. because, 50 wt. 95, 75 wt. 95, 95 wt. 95 or 98 wt. 95.

The solid dispersion can be used as a dosage form by itself or it can serve as a product for use in production (MOP) in the preparation of other dosage forms such as capsules, tablets, solutions or suspensions. An example of an aqueous suspension is an aqueous suspension of 1:1 (wt/wt), dried by spraying a dispersion of compounds NRMSAZ-NE, containing 2.5 mg/ml of the compound in 2 95 polysorbate-80. Solid dispersions for use in a tablet or capsule are usually mixed with other excipients or adjuvants, which are usually found in such dosage forms. For example, a typical capsule filler contains a 2:1 (wt/wt) spray-dried dispersion of the compound?NRMSA5B-ME (60 95), lactose (fast-flowing) (15 95), microcrystalline cellulose (for example, Amise!.vir. (HO-102) (15.8 95), sodium starch (7 95), sodium lauryl sulfate (2 90) and magnesium stearate (1 Ob).

NRMSAFZ polymers are available in low, medium and high gradation as Adoa.zir.(A)-Г E,

Adoai.zir.(A)-ME and Adoai.z,ir.(A)-NE, respectively from Zpip-Eiva Spetis! So., I. TO, ToKuo, Huarap.

Predominantly high-quality ME and NE are used.

The following paragraphs describe examples of drugs, dosages, etc., useful for animals, not humans. Administration of compounds of the invention and combinations of compounds of the invention with antiobesity agents may be administered orally or by other means.

The amount of a compound of the invention or a combination of a compound of the invention with another anti-obesity agent administered provides an effective dose. In general, the daily dose administered orally to the animal is in the range of from about 0.01 to about 1,000 mg/kg of body weight, for example from about 0.01 to about 300 mg/kg or from about 0.01 to about 100 mg/kg or from about 0.01 to about 50 mg/kg body weight or from about

0.01 to about 25 mg/kg, or from about 0.01 to about 10 mg/kg, or from about 0.01 to about 5 mg/kg.

Conveniently, the compound of the invention (or combination) can be added to drinking water so that a therapeutic dose of the compound is taken with a daily portion of water. The compound can be directly metered into drinking water, preferably in the form of a liquid, water-soluble concentrate (such as an aqueous solution of a water-soluble salt).

It is convenient that the compound according to the invention (or combination) can be directly added to the food as such or in the form of a food supplement for the animal, which is also indicated as a ready mixture or concentrate. A ready mixture or concentrate of a compound in an excipient, diluent, or carrier is more commonly used to incorporate the agent into food. Acceptable excipients, diluents or carriers are liquid or solid, as appropriate, such as water, various flours such as alfalfa meal, soybean meal, cottonseed meal, linseed meal, corn cob meal and corn meal, molasses, urea, bone meal and mineral mixtures, such as are commonly used for animal feed. A suitable animal food is a particularly effective excipient, diluent or carrier; that is, a small portion of such food. The carrier facilitates uniform distribution of the compound in the final food with which the finished mixture is mixed. Preferably, the compound is mixed well with the finished mixture and then with the food. In this regard, the compound is dispersed or dissolved in an acceptable oily solvent such as soybean oil, corn oil, cottonseed oil, etc., or in a volatile organic solvent and then mixed with a carrier. It is understood that the proportions of the compound in the concentrate can vary over a wide range, since the amount of the compound in the final food can be adjusted by admixing an acceptable proportion of the finished mixture to the food to obtain the desired level of the compound.

Highly concentrated concentrates can be mixed by the food manufacturer with a protein carrier such as soybean meal and other flours as described above to produce concentrated supplements suitable for direct animal consumption. In such cases, animals are allowed to have a normal diet. Alternatively, such concentrated supplements may be added directly to food to produce a nutritionally balanced final food containing a therapeutically effective level of a compound of the invention. The mixtures are thoroughly mixed using standard techniques, such as a two-blade blender, until completely homogenous.

When the additive is used as an impregnating agent for food, it helps ensure uniformity of distribution of the compound throughout the impregnated food.

Drinking water and food effective for increasing the formation of lean meat and for improving the ratio of fat in lean meat are usually prepared by mixing a compound of the invention with a sufficient amount of animal food, obtaining a content of the compound in the food or water from about 103 to about 500 m.h.

Preferably, the feed of pigs, cows, sheep and goats to be treated will typically contain from about 1 to about 400 grams of the compound of the invention (or combination) per ton of feed, the optimum amount for these animals typically being from about 50 to about 300 grams per ton food

Preferably, poultry and pet food typically contains from about 1 to about 400 grams and preferably from about 10 to about 400 grams of the compound of the invention (or combination) per ton of food.

For parenteral administration to an animal, the compounds of the invention (or combination) are prepared in the form of a paste or pellet and administered as an implant, usually under the scalp or ears of the animal, in which the formation of lean meat is increased and the ratio of fats in the lean meat is improved.

Paste preparations can be obtained by dispersing the drug in a pharmaceutically acceptable oil, such as peanut oil, sesame oil, corn oil, etc.

Pellets containing an effective amount of a compound of the invention, pharmaceutical composition or combination may be prepared by mixing the compound of the invention or combination with a diluent such as beeswax, carnauba wax, etc. and a lubricant such as magnesium or calcium stearate which may be added to improve the pelleting process.

It is generally understood that more than one pellet may be administered to an animal to achieve the desired dose level, which will provide an increase in the desired lean meat formation and an improvement in the fat ratio of the lean meat. However, implants may also be administered intermittently during the animal's treatment in order to maintain an appropriate level of drug in the animal's body.

The invention has several advantages in veterinary use. For pet owners or veterinarians wishing to reduce weight and/or remove unwanted fat from animals, the invention provides a means by which this can be accomplished. For poultry keepers,

cows and pigs, using the method according to the invention will produce leaner animals that command a higher price in the meat market.

EXAMPLES

Unless otherwise noted, starting materials are usually obtained from commercial sources such as AIdgisp Spetis!5 So. (Mim'"aiykeye, UM), Hapsazieg 5zupipeviv, Ips. (UMipapat, MN), Asgo5 Ogdapisv (Raiyamup, MU), Maubgidde SNetisai Sotrapu, CYA. (Sogpulaii, Epdiapa) and Tudeg Zsiepiyis (Rgipseiop, MU). Some use common abbreviations and acronyms that include: ASON (acetic acid), OWL (1,8-diazabicyclo/5.4.01undec-7-ene), SOY (1,1"-carbonyldiimidazole), DCM (dichloromethane), DEA (diethylamine) , OMAR (4-dimethylaminopyridine), DMF (M, M-dimethylformamide), DMSO (dimethylsulfoxide), EOSI /(M-(3-dimethylaminopropyl)-M'-ethylcarbodiimide), EBO (diethyl ether), EMOAc (ethyl acetate), EN (ethanol), NATI (hexafluorophosphate 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methanaminium), NVTO (hexafluorophosphate O-benzotriazol-1-yl-M, M,M ",M'-tetramethyluronium), nov (1-hydroxybenzotriazole), IPS (isopropyl alcohol), КНМО5 (potassium hexamethyldisilazane), MEON (methanol), MTBE (tert-butyl methyl ether), Mavn(OAs)z (sodium triacetoxyborohydride), manmo5z (sodium hexamethyldisilazane), MMP (M-methylpyrrolidone), ZEM (2- (three methylsilyl)ethoxy|methyl), TFO (trifluoroacetic acid), THF (tetrahydrofuran) and TzR (propanephosphonic anhydride).

The reactions were carried out in air or, when oxygen- or moisture-sensitive reagents or intermediates are used, in an inert atmosphere (nitrogen or argon). When appropriate, the reaction devices were dried under dynamic vacuum using a heat gun and anhydrous solvents were used (Zyge-Zea!"M products from Aidgispy Spetis! Sotrapu, Miim"aikeee, Umizsopvip or Ogiboim"M products from EMO Spetisai5, (ibb5iom/p , MU). Commercial solvents and reagents were used without further purification. When indicated, reactions were heated using microwave radiation using Vioiade Ipyiaug microwave units or

Regzopa! SPetibigu Etiub5 Oriitigeg. The progress of the reactions was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LC-MS), high-performance liquid chromatography (HPLC), and/or gas chromatography-mass spectrometry (GC-MS). TLC was performed on plates coated with silica gel with an indicator

From fluorescence (with an excitation wavelength of 254 nm) and visualization in UV light and/or using g, KMpO»4, CoSi», phosphomolybdic acid and/or cerium ammonium molybdate.

LC-MS data were obtained on an Adiyepi 1100 Zegie5 device with automatic sampling of I ear

Tesppodie5, Setipi C18 columns, MeSM/water and or TFO gradients, formic acid or ammonium hydroxide. Column eluents were analyzed using a mass spectrometer

Uumaiitege 20), which scans both positive and negative ions from 100 to 1200 Da. Other similar devices were also used. HPLC data were obtained on an Adiiepi 1100 Zegiev instrument using Setipi or HVgidde C18 columns, MeSM/water gradients and modifiers or

TFO, or ammonium hydroxide. GC-MS data were obtained using a Neu/Lei RuskKaga 6890 thermostat with an HP 6890 injector, an HP-1 column (12 mx0.2 mmx0O.33 μm) and helium as a carrier gas. The sample was analyzed on a mass-selective detector HP 5973 with scanning from 50 to 550 Da, using electron ionization. Purifications were carried out with the help of medium-performance liquid chromatography (MELC), using the devices of Isso Sotbrigiazi! Sotrapiope, Apai rest

IpteiPERiIazp 280, Vioiade 5R1I or Vioiade Izoiega Ope and prepackaged silica gel cartridges Isso Cadizer or Vioiade Zpar. Chiral purification was carried out using chiral supercritical liquid chromatography (SLC) using Wegdeg or Tag devices; columns

Spiga!RAK-AO, -A5, -IS, SpigaiseI-0OO or -07; and mixtures of CO" with Meon, EN, iRgOH or mesm, separately or modified TFO or iRgMN". UV detection was used to trigger collection of fractions.

Mass spectrometry data were obtained from LC-MS analyses. Mass spectrometry (MS) was carried out using a source of chemical ionization at atmospheric pressure (ARSI), electrospray ionization (EI), electron impact ionization (EI) or electron scattering ionization (E5).

Proton nuclear magnetic resonance (H NMR) spectra were recorded in parts per million in the weak field region from tetramethylsilane on Magiap 300, 400, 500, or 600 spectrometers

MHz. Chemical shifts were expressed in parts per million (ppm) relative to the residual peaks of the deuterated solvent. Peak shapes are described as: c, singlet; d, doublet; t, triplet; kv, quartet; queen, quintet; m, multiplet; w c, wide singlet; kind, visible Analytical WPP data were obtained on the Wegdeg analytical device as described above. Optical rotation data were obtained on a Re KkipEIteg model 343 polarimeter, using a 1 dm cuvette.

Silica gel chromatography was performed initially using Viotiade or I5SO medium pressure systems on columns prepacked by various commercial suppliers, including Viotiade and IZSO. Microanalyses were performed using

Otsapiyaime Tesppoiodiez Ips. and they were within 0.4 95 of the calculated values.

Unless otherwise stated, chemical reactions were performed at room temperature (approximately 23 degrees Celsius).

The compounds and intermediates described below were named using the naming conventions and applying SpetVioOgam Oga, Version 12.0 (Satgiddezoy Sogr., Satbgidde, Mazzaspizeiv).

The naming convention provided in SPpetVioYUOgam/ShkKga, Version 12.0 is well known to one skilled in the art, and it is believed that the naming convention provided in

SpetVioOgam OGga, Version 12.0, is generally consistent with ISRAS (International Union of Theoretical and Applied Chemistry) recommendations on nomenclature in organic chemistry and CA5 rules

Ipdeh Unless otherwise indicated, all reagents were obtained from commercial sources without further purification or obtained using methods known in the literature.

The terms "concentrated", "evaporated" and "concentrated in vacuo" refer to the removal of solvent under reduced pressure in a rotary evaporator with a bath temperature of less than 60°C. Abbreviation "min." and "hr." stand for "minutes" and "hours", respectively. The term "TLC" refers to thin-layer chromatography, "room temperature" refers to temperatures between 18 and 252C, "GC-MS" refers to gas chromatography-mass spectrometry, "LC-MSO" refers to liquid chromatography-mass spectrometry, "UEC" refers to ultra-performance liquid chromatography and "HPLC" refers to high performance liquid chromatography, "ZES" refers to supercritical liquid chromatography.

Hydrogenation can be carried out in a Parr shaker under the pressure of hydrogen gas or in a hydrogenation device in a Tpaiz-papo H-Sire flow with full hydrogen filling and a flow rate of 1-2 ml/min at a given temperature.

The retention times of HPLC, UEC, LC-MS, GC-MS, and 5ES were measured using the methods specified in the methods.

Preparation of intermediate compounds and examples

General Procedure A: Add diisopropylethylamine (3.0 eq.) to a solution of intermediate 1 or intermediate 2 (1 eq.) in dimethylformamide or tetrahydrofuran (0.15 M). NATI (1.0 equiv.) and the corresponding amine (2.0 equiv.) were added sequentially to the vessel. Reaction mixture

The solution was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified using preparative HPLC to give the specific product unless otherwise noted.

General Procedure B: Add oxalyl chloride (2.0 equiv, 2M in dichloromethane) to a suspension of intermediate 1 or intermediate 2 (1.0 equiv) in dichloromethane (0.1M).

Dimethylformamide (10 μl) was added to the suspension, and the reaction mixture was stirred at room temperature for 30 minutes. The suspension returned to the solution during this time. The appropriate amine (1.0 eq.) and diisopropylethylamine (2.3 eq.) in dichloromethane (0.5 mL) were added to the reaction mixture and stirred at room temperature for 16 h.

The reaction mixture was diluted with dichloromethane (2 mL) and washed successively with 1 M sodium hydroxide (100 μL) and saturated saline (100 μL). The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC to afford the specific product unless otherwise noted.

Intermediate 1: 2-(5-(3-ethoxypyridin-2-yl/oxy)pyridin-3-yl)/pyrimidine-o-carboxylic acid

And that's it

M

Stage 1: 3-Ethoxypyridine

Cesium carbonate (12 mol, 1.5 equiv.) and ethyl iodide (9.7 mol, 1.2 equiv.) were added to a solution of 3-hydroxypyridine (8.10 mol, 1.0 equiv.) in acetone (12 L) at 15 "C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the organic layer was concentrated to give the crude product. Ethyl acetate (20 L) was added and washed with water (3 x 5 L). The organic layer was dried over sodium sulfate , filtered and concentrated to give 3-ethoxypyridine (620 g, 62 90) as an oil. "H NMR (400 MHz, SOSI") b 1.44 (t, ЗН), 4.07 (q, 2Н), 7 ,15-7.23 (m, 2H), 8.20 (dd, 1H), 8.30 (d, 1H).

Step 2: 3-Ethoxypyridine-1-oxide t-Chloroperoxybenzoic acid (6.5 mol, 1.3 equiv) was added to a solution of 3-ethoxypyridine (5.0 mol, 1.0 equiv) in dichloromethane (12 L) at 10 "C. The reaction mixture was stirred at room temperature for 24 hours. Sodium thiosulfate (4 kg, in 5 liters of water) was added.

The reaction mixture was stirred at 15 "C for 2 hours. Another part of sodium thiosulfate (1.5 kg, in 5 l of water) was added. The reaction mixture was stirred at 15 "C for 1 hour.

The mixture was extracted with dichloromethane (16 x 10 L). The combined organic layers were concentrated to give the crude product. The crude product was purified by silica gel column chromatography (dichloromethane:methanol; 100:1-10:1) to give the title compound (680 g, 97 ov) as a brown oil. The obtained was further purified by trituration with petroleum ether (4 L) at room temperature for 24 hours to give 3-ethoxypyridine-1-oxide (580 g, 83 95) as a yellow solid. "H NMR (400 MHz, SOSI") b 1.41 (t, ЗН), 4.02 (q, 2Н), 6.84 (dd, 1Н), 7.12 (dd, 1Н), 7.85 (d, 1H), 7.91-7.95 (m, 1H).

Stage 3: 2-(5-Bromopyridin-3-yl)oxy)-3-ethoxypyridine

This reaction was carried out in five parallel batches.

Diisopropylethylamine (2.69 mol, 3.7 eq.) and bromotripyrrolidinophosphonium hexafluorophosphate (0.93 mol, 1.3 eq.) were added to a stirred solution of 3-ethoxypyridine-1-oxide (0.72 mol, 1.0 eq.). ) and 3-bromo-5-hydroxypyridine (0.72 mol, 1.0 equiv.) in tetrahydrofuran (2500 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 days, then individual batches were combined into one batch. The resulting suspension was concentrated to dryness and dissolved in dichloromethane (25 L). The organic layer was washed with 1M sodium hydroxide (15 L), water (3 x 20 L), and saturated saline (20 L). The organic layer was dried over sodium sulfate, filtered and concentrated to give an oil. The crude oil was purified using silica gel column chromatography (petroleum ether: ethyl acetate; 10:1-1:1) to give the crude product as a brown solid. This solid was triturated with methyl tert-butyl ether:petroleum ether (1:10; 11 L) to give 2-((5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (730 g, 69 95) in in the form of an almost yellow solid. "H NMR (400 MHz, SOSIZz) b 1.49 (t, ЗН), 4.16 (q, 2Н), 7.04 (dd, 1Н), 7.25 (dd, 1Н), 7.68- 7.73 (m, 2H), 8.44 (d, 1H), 8.49 (d, 1H). MS (ESxh) 2971

Koo) (M--N).

Step 4: Ethyl 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5o-carboxylate

A solution of /2-(5-bromopyridin-3-yl)oxy)-3-ethoxypyridine (300 mmol, 1.0 equiv) in tetrahydrofuran (1.3 L) was degassed with nitrogen for 30 minutes. Turbo Grignard (390 mmol, 1.3 equiv, 1.3 M in tetrahydrofuran) was added at room temperature at a rate to maintain the internal temperature below 30 °C. The reaction mixture was allowed to cool to room temperature and stirred for 3 hours. the mixture was cooled to 10 °C, and zinc chloride (390 mmol, 1.3 eq., 1.9 M in 2-methyltetrahydrofuran) was added at a rate to maintain the temperature below 15 °C. The resulting suspension was warmed to room temperature until all the precipitate did not dissolve, and then cooled again to 10 C. Ethyl 2-chloropyrimidine-o-carboxylate (360 mmol, 1.2 equiv.) and dichloro(|bis(2-(diphenylphosphino)phenyl)ether|palladium(II) (6.00 mmol, 0.02 equiv.) was added as solids. The resulting suspension was degassed with nitrogen for 30 minutes, then heated to 50 C for 16 hours. The reaction mixture was collected under aqueous conditions, then treated sequentially with ethylenediaminetetraacetate disodium salt acids, silica thiooxide yu, and charcoal to remove metal impurities. The crude compound was recrystallized from methanol (450 mL) to give ethyl 2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (77 g, 70 95) as a light, yellow solid. "H NMR (400 MHz, SOSI") b 1.44 (t, ЗН), 1.50 (t, ЗН), 4.19 (sq, 2H), 4.46 (sq, 2H), 7.00 -7.04 (m, 1H), 7.25 (s, 1H), 7.71 (d, 1H), 8.59 (s, 1H), 8.66 (d, 1H), 9.32 ( c, 2H), 9.55 (c, 1H).

Step 5: 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

Sodium hydroxide (307 mmol, 1.5 eq., 4M aqueous) and methanol (50 mL) were added to a suspension of 2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidin-5- carboxylate (205 mmol, 1.0 equiv.) in tetrahydrofuran (300 mL). The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (400 ml) and extracted with a mixture of 2:1 diethyl ether-heptane (2 x 300 ml). The aqueous layer was acidified to pH 4 with 4M hydrochloric acid. The resulting suspension was stirred at room temperature for 1 hour. The solid was filtered, washed with water, and dried to give 2-(5-(3-ethoxypyridin-2-yl)uoxy)pyridin-3-yl)/pyrimidine-o-carboxylic acid (69 g, 100 95) as a light , a yellow solid. "H NMR (400 MHz, DMSO-av) 61.37 (t, ZN),

4.18 (q, 2H), 7.19 (dd, 1H), 7.58 (dd, 1H), 7.70 (dd, 1H), 8.35-8.40 (m, 1H), 8 .66 (d, 1H), 9.33 (s, 2H), 9.41 (d, 1H), 13.9 (w s, 1H).

Intermediate 2: 3-15-(3-Ethoxypyridin-2-yl)oxy|pyridin-3-yl)-1,2,4-triazine-6-carboxylic acid

F Y to a" mg dream

M

Stage 1. 6-Bromo-1,2,4-triazine-3-amine

Water (120 mL) was added to a mixture of 3-amino-1,2,4-ryazine (104 mmol, 1.0 equiv) in acetonitrile (120 mL) and stirred at room temperature until a brown solution was formed. The mixture was cooled to 0 °C, treated in portions with M-bromosuccinimide (109 mmol, 1.05 equiv.) and stirred at 0 °C for 20 min. After warming to room temperature, the mixture was diluted with ethyl acetate (350 mL) and cooled to 0 °C. Sodium carbonate (12 g) was added to the mixture and stirred for 10 min. The two layers were separated, and the aqueous phase was extracted with ethyl acetate (200 mL). The combined organic layers were washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to afford b-bromo-1,2,4-triazin-3-amine (10.5 g, 58 95) as a yellow solid. N

NMR (400 MHz, COzOb) 8.32 (s, 1H).

Stage 2. Ethyl 3-amino-1,2,4-triazine-6-carboxylate

In two separate batches, palladium acetate (0.87 mmol, 0.05 eq.) was added to a solution of 6-bromo-1,2,4-triazin-3-amine (17 mmol, 1.0 eq.), triethylamine ( 35 mmol, 2.0 eq.), and xanthophos (1.40 mmol, 0.08 eq.) in ethanol (60 mL) was added. The mixture was degassed with carbon monoxide and stirred at 85°C under carbon monoxide (16 psi) for 16 h.

The cooled reaction mixture was diluted with ethyl acetate (60 mL), filtered through a pad of Celite and concentrated. The crude products from both batches were combined and purified by column chromatography (ethyl acetate/petroleum ether - 3:7) to give ethyl 3-amino-1,2,4-triazine-6-carboxylate (2.5 g, 88 95 ) in the form of a yellow solid. "H NMR (400 MHz, SOSI") 5 1.49 (t,

ЗН), 4.50 (sq., 2H), 8.79 (s, 1H).

Stage 3. ethyl 3-chloro-1,2,4-triazine-6-carboxylate tert-Butyl nitrite (4.5 mmol, 1.5 equiv.) was added dropwise to a solution of ethyl 3-amino-1,2,4- of triazine-6-carboxylate (3.0 mmol, 1.0 equiv.) and copper (II) chloride (3.6 mmol, 1.2 equiv.) in

From acetonitrile (15 ml). The resulting mixture was heated at 60 "C for 1 hour.

The reaction mixture was cooled to room temperature and treated with cold hydrochloric acid (10 mL, 1M). The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography eluting with ethyl acetate/petroleum ether (5:95 to 1:1) to give ethyl 3-chloro-1,2,4-triazine-6-carboxylate (300 mg, 54 95) as yellow solid. "H NMR (400 MHz, SOSI") b 1.50 (t, ЗН), 4.58 (q, 2Н), 9.11 (s, 1Н).

Stage 4. 3-Ethoxy-2-C5-(tributylstananyl)pyridine-3-yl|oxy)pyridine

Tetra(triphenylphosphine)palladium(0) (0.68 mmol, 0.10 eq.) was added to a solution of 2-((5-bromopyridin-3-yl)oxy|H-3-ethoxypyridine (6.8 mmol, 1, 0 equiv.) and hexabutyldistanan (7.5 mmol, 1.1 equiv.) in dioxane (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 110 "C and stirred at this temperature for 16 h. The mixture was quenched with aqueous potassium fluoride and stirred for 1 h. The resulting suspension was filtered through a pad of celite, and the filtrate was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated.

The crude product was purified by column chromatography (ethyl acetate/petroleum ether - from 0:100 to 1:4) to give 3-ethoxy-2-C5-(tributylstananyl)pyridin-3-yl|oxy)pyridine (1.6 g, 47 95) in the form of yellow oil. "H NMR (400 MHz, SOSIiz") b 0.88 (t, 9H), 1.06-1.11 (m, 6H), 1.32 (s, 6H), 1.47-1.58 ( m, 9H), 4.17 (q, 2H), 6.99 (dd, 1H), 7.22 (dd, 1H), 7.57 (dd, 1H), 7.70 (dd, 1H), 8.37-8.40 (m, 2H).

Stage 5. Ethyl 3-5-|(3-ethoxypyridin-2-yl)oxy|pyridin-3-yl)-1,2,4-triazine-6-carboxylate

Tetra(triphenylphosphine)palladium(0O) (0.05 mmol, 0.05 eq.) was added to a mixture of 3-ethoxy-2-1(5-(tributylstananyl)pyridine-3-yl|oxy)pyridine (0.99 mmol , 1.0 equiv.) and ethyl 3-chloro-1,2,4-triazine-b-carboxylate (0.99 mmol, 1.0 equiv.) in dioxane (8 mL). The vessel was degassed to remove oxygen by gently bubbling nitrogen gas for 2 min. The container was then stirred at 115 °C for 30 min under the influence of microwave radiation. The reaction mixture was cooled to room temperature, treated with aqueous potassium fluoride, and stirred for 1 h. The suspension was filtered through a pad of celite, and the filtrate was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. -2-yl)oxy|pyridin-3-yl)-1,2,4-triazine-6-carboxylate (150 mg, 41 90) as a yellow oil. MS (EC-) 368.0 (M'-H ).

Stage 6. 3-15-(3-ethoxypyridin-2-yl)oxy|pyridin-3-yl)-1,2,4-triazine-6-carboxylic acid

Sodium hydroxide (1.0 mmol, 20 equiv., 2M) was added to a solution of ethyl 3-15-(3-ethoxypyridin-2-yl)oxy|pyridin-3-yl)-1,2,4-triazin-6- carboxylate (0.053 mmol, 1.0 equiv.) in methanol (1 mL) at room temperature. The solution was stirred for 1 hour. The mixture was concentrated to remove methanol, diluted with water, and extracted with dichloromethane (2 x 15 mL). The aqueous layer was acidified to pH-5 with 2 M hydrochloric acid and extracted with ethyl acetate (3 x 10 ml).

The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give the product (15 mg, 83 Fo) as a pale yellow solid. MS (EC k) 339.9 (MN).

Intermediate 3: 2-(5-((3-ethoxypyrazin-2-yl)/oxy|pyridin-3-yl/pyrimidine-5-carboxylic acid

Mb o fi tya rya

M

Step 1. 2-(5-Bromopyridin-3-yl)oxy|-3-ethoxypyrazine 5-Bromopyridin-3-ol (32 mmol, 1.0 equiv.) and cesium carbonate (39 mmol, 1.3 equiv.) was added to a solution of 2-chloro-3-ethoxypyrazine (32 mmol, 1.0 equiv.) in M-methyl-2-pyrrolidone (250 mL). The reaction mixture was stirred at 150 °C for 1 h. The cooled reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified using column chromatography eluting with petroleum ether/ethyl acetate (0 95 to 100 95) to afford the title compound (5.0 g, 54 95) as a white solid. "H NMR (400 MHz,

Co., Ltd.) SOFI") b 1.50 (t, ZN), 4.54 (q, 2H), 7.59 (d, 1H), 7.77 (t, 1H), 7.83 (d, 1H) , 8.49 (d, 1H), 8.56 (d, 1H).

Stage 2. Ethyl 2-15-((3Z-ethoxypyrazin-2-yl)oxy|pyridin-3-yl)pyrimidine-5-carboxylate

P,1-Bis(idiphenylphosphino)ferrocene|dichloropalladium (II) complex with dichloromethane (124 mg, 0.05 eq.) was added to a suspension of 2-(5-bromopyridin-3-yl)oxy)-3-ethoxypyrazine (3, 4 mmol, 1.0 equiv), bis(pinacolato)diboron (4.1 mmol, 1.2 equiv), and potassium acetate (13 mmol, 4.0 equiv) in dioxane (5 mL). The reaction mixture was purged with nitrogen and stirred at 100 °C for 2 hours.

The reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (25 mL) and washed with saturated saline (3 x 50 mL).

The organic layer was concentrated to give //2-ethoxy-3-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)oxy)pyrazine ( 1.4 g, 11095) in the form of black oil, which was used directly in the next stage.

Ethyl 2-chloropyrimidine-5-carboxylate (930 mg, 1.2 equiv.), potassium carbonate (1.1 g, 2.0 equiv.), and

P,1-bisidiphenylphosphino)ferrocene|dichloropalladium (II) complex with dichloromethane (150 mg, 0.05 equiv.) was added to a solution of 2-ethoxy-3-((5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolane-2-yl)pyridine-

C-yl)oxy)pyrazine (1.4 g, 4.1 mmol) in dioxane (5 mL). The black suspension was purged with nitrogen and stirred at 80 "C for 16 hours. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (25 mL), washed with brine (3 x 50 mL), and dried to black The crude material was purified by flash chromatography (ethyl acetate in petroleum ether) to afford ethyl 2-15-(3-ethoxypyrazin-2-yl)/oxy|pyridine-3-ylpyrimidine-5-carboxylate (700 mg, 4695) in in the form of a yellow solid, MS (EC) 367.9 (INN).

Stage 4. 2-15-(3-ethoxypyrazin-2-yl)uoxy|pyridin-3-ylpyrimidine-5-carboxylic acid

Sodium hydroxide (6.8 mmol, 5.0 eq., 2M) was added to ethyl 2-15-(3-ethoxypyrazin-2-yl)oxy|pyridin-3-ylpyrimidine-5-carboxylate (1.4 mmol, 1 .0 equiv.) in ethanol (5 mL). The reaction mixture was stirred at 30°C for 16 hours. Methyl tert-butyl ether (30 mL) was added to the reaction mixture, and the resulting solid was filtered and dried to give 2-(5-((3-ethoxypyrazine-2- yl)/oxy|Ipyridine-3-ylpyrimidine-5-carboxylic acid (500 mg, 101 95) in the form of sodium salt. "H NMR (300 MHz, DMSO-α) 6 1.42 (t, ЗН), 4 ,48 (sq, 2H), 7.67 (s, 1H), 7.93 (s, 1H), 8.54 (s, 1H), 8.74 (s, 1H), 9.33 (s, 2H), 9.45 (s, 1H).

Intermediate 4: 2-(5-(3-(2-Fluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

F. Y

Byto a" rya

M

Stage 1: 3-(2-Fluoroethoxy)pyridine

Potassium carbonate (1.5 g, 2.0 equiv.) was added to a solution of 3-hydroxypyridine (500 mg, 1 equiv.) and 1-fluoro-2-iodoethane (920 mg, 1.0 equiv.) in dimethylformamide (10 ml). The suspension was stirred at 30 "C for 16 hours. The reaction mixture was diluted with 10 95 methanol in dichloromethane (90 mL) and washed with water (20 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The crude material was purified using flash chromatography (gradient: 0-4.595 methanol in dichloromethane) to give /-3-(2-fluoroethoxy)pyridine (500 mg, 67 95) as a brown oil. "H NMR (400 MHz, SOCI") b 4.19- 4.33 (m, 2H), 4.67-4.74 (m, 1H), 4.79-4.86 (m, 1H), 7.22 (dd, 2H), 8.24 (t, 1H), 8.34 (t, 1H).

Step 2: 3-(2-Fluoroethoxy)pyridine 1-oxide t-Chloroperoxybenzoic acid (2.49 g, 1.2 equiv) was added to a solution of 3-(2-fluoroethoxy)pyridine (1.7 g, 1.0 equiv) .) in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified directly by flash chromatography (gradient: 0-5 96 methanol in dichloromethane) to give 3-(2-fluoroethoxy)pyridine 1-oxide (1.2 g, 63 95) as a white solid. "H NMR (400 MHz,

SObsIi») b 4.16-4.22 (m, 1H), 4.23-4.29 (m, 1H), 4.66-4.73 (m, 1H), 4.77-4.84 (m, 1H), 6.90 (dd, 1H), 1.17 (dd, 1H), 7.87-7.94 (m, 1H), 7.99 (t, 1H).

Stage 3: 2-(5-Bromopyridin-3-yl)oxy)-3-(2-fluoroethoxy)pyridine

Diisopropylethylamine (5.2 mL, 3.8 equiv.) was added to a solution of 3-(2-fluoroethoxy)pyridine 1-oxide (1.2 G, 1.0 equiv.), 3-bromo-5-hydroxypyridine (1, 3 g, 1.0 equiv.) (and bromotripyrrolidinophosphonium hexafluorophosphate (4.6 g, 1.3 equiv.) in tetrahydrofuran (25 mL) at 13 °C. The mixture was stirred at room temperature for 16 hours. The reaction mixture

Zo was quenched with water (20 mL) and extracted with ethyl acetate (50 mL). The combined organic layers were washed with saturated ammonium chloride solution (3 x 20 mL) and saturated saline (100 mL), dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (gradient: 0-70 90 ethyl acetate in petroleum ether) to give 2-((5-bromopyridin-3-yl)oxy)-3-(2-fluoroethoxy)pyridine (1.9 g, 81 95) in the form of yellow oil. "H NMR (400 MHz, SOSI") b 4.28 - 4.33 (m, 1H), 4.34 - 4.41 (m, 2H), 4.70 - 4.78 (m, 1H), 4.82-4.82 (m, 1H), 7.05 (dd, 1H), 7.31 (dt, 1H), 7.69 - 7.73 (m, 1H), 7.74 - 7, 80 (m, 2H), 8.44 (dd, 1H), 8.48-8.52 (m, 2H).

Step 4: 2-(5-(3-(2-Fluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

Bis(pinacolato)udibor (580 mg, 1.2 eq.), potassium acetate (560 mg, 3.0 eq.), and (1,1- bisidiphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (70 mg, 0.05 eq.) was added to a solution of 2-((5-bromopyridin-3-yl)/oxy)-3-(2-fluoroethoxy)pyridine (600 mg, 1.0 eq.) in dioxane (10 mL) at room temperature. The reaction mixture was stirred at 100 "C for 16 hours. The reaction mixture was diluted with ethyl acetate (60 mL), washed with water (20 mL) and saturated brine, then concentrated to a residue. The residue was diluted with dioxane (15 mL) and water (5 mL). Ethyl 2-chloropyrimidine-5-carboxylate (310 mg, 1.0 equiv.), (1,1"- bisidiphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (61 mg, 0.05 equiv.), and potassium carbonate (460 mg, 2.0 equiv.) was added to the reaction mixture, and the resulting suspension was stirred at 80 °C for 16 hours. The suspension was filtered and then partitioned between ethyl acetate (30 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 30 mL).The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a crude material which was purified by preparative TLC (5595 methanol in dichloromethane) to give 2- (5-(3-(2-fluoroethoxy)pyridin-2-yl)/oxy)pyridin-3-yl)pyrimidine-5-carbons into acid (80 mg, 13 95). MC (EC) 357.0 (MAN).

Example 1: (5)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)upyrimidine-5-carboxamide and: o)

M gu Ho yo lk:

N

M

Oxalyl chloride (13.8 mL, 160 mmol, 1.2 equiv) and dimethylformamide (0.510 mL, 6.65 mmol, 0.05 equiv) were added to a suspension of 2-(5-(3-ethoxypyridin-2-yl) oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid (45.0 g, 133 mmol, 1.0 eq.) in dichloromethane (500 mL). The suspension was stirred for 2 hours until a solution was reached. The reaction mixture was concentrated to give the crude acid chloride as a red solid. A solution of (5)-tetrahydrofuran-3-amine (12.2 g, 140 mmol, 1.05 equiv.) and diisopropylethylamine (51.0 mL, 293 mmol, 2.2 equiv.) in tetrahydrofuran (100 mL) was added dropwise to a solution of crude acid chloride in dichloromethane (200 mL) at 0 "C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. Water (1.0 L) and ethyl acetate (600 mL) were added, and the organic layer was separated, washed with saturated sodium bicarbonate, dried over magnesium sulfate, and filtered. The filtrate was treated with activated carbon (20 g) and stirred at 65 "C for 20 minutes. The suspension was filtered warm, and the filtrate was concentrated to a light yellow solid, which was recrystallized from methanol in ethyl acetate (1:4, 1 L) to give (5)-2-(5-((3-ethoxypyridin-2-yl)oxy )pyridin-3Z-yl)-

M-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (43.5 g, 81 95) as a colorless solid. The title compound was combined with previous batches (108.7 g, 266.8 mmol) obtained by the same method and suspended in ethyl acetate (1.0 L) at 80°C for 4 hours. The suspension was allowed to cool to room temperature and stirred for 4 days. the solid was filtered, washed with ethyl acetate (3 x 200 mL) and dried under high vacuum at 50"C for 24 hours to give (5)-2-(5-(3-ethoxypyridin-2-yl)uoxy )pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (100.5 g, 92 95) as a colorless solid. "H NMR (300 MHz, DMSO-sbv) 5 1.38 (t, ЗН), 1.89-1.98 (m, 1Н), 2.15- 2.26 (m, 1Н), 3.65 (dd, 1H), 3.70-3.78 (m, 1H), 3.85-3.92 (m, 2H), 4.18 (q, 2H), 4.46-4.55 (m , 1H), 7.18 (dd, 1H), 7.58 (dd, 1H), 7.69 (dd, 1H), 8.37 (dd, 1H), 8.64 (d, 1H), 8 .95 (d, 1H), 9.28 (s, 2H), 9.39 (d, 1H). MS (EC) 408.4 (MN). Melting point 177.5 "C. Elemental analysis for

Co) Ca On M50x: calculated C, 61.91; H, 5.20; M, 17,19; found C, 61.86; H, 5.18; M, 17.30.

The solid form from this procedure was characterized using powder X-ray diffraction analysis (XRD) and designated as form 1.

Optional preparation for (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (Example 1)

A 100 mL reactor was charged with acetonitrile (35 mL), 2-(5-(3-ethoxypyridin-2-yl)uoxy)pyridin-3-yl)pyrimidine-o-carboxylic acid (5.0 g, 15 mmol) and ( 5)-tetrahydrofuran-3-amine hydrochloride (2.2 g, 18 mmol, 1.2 equiv.). Diisopropylethylamine (18 mL, 103 mmol, 7.0 equiv.) was charged while maintaining the temperature from 20°C to 30°C. A solution of propanephosphonic anhydride (PPA) in acetonitrile (21 mL, 30 mmol, 2.0 equiv) was charged at a rate to maintain the temperature below 45 °C. The reactor was heated to 40-57 °C for 1 h, then sampled for completion reactions. The reaction mixture was cooled to 20°C to 25°C, and tetrahydrofuran (25 mL) was added. Sodium bicarbonate solution (0.5M, 40 mL) was charged, and the mixture was stirred for 1 hour.

pH was monitored and measured at 8.5. Ethyl acetate (40 mL) was added and the mixture was stirred for 15 minutes. The mixture was left, and the phases were separated. The aqueous layer was transferred to a separatory funnel and extracted again with ethyl acetate (100 mL). The organic phases were combined and washed with water (40 mL). The organic layer was transferred to a 100 ml reactor in portions and concentrated in vacuo to a low volume. Methyl ethyl ketone (100 mL) was added and the mixture was concentrated to a final volume of approximately 60 mL. The vacuum was removed, and the suspension was heated at reflux and held until the solids were washed off the walls of the reactor. The suspension was cooled to 15 "C for 2 hours and granulated overnight. The solids were collected by filtration, the reactor and cake were washed twice with methyl ethyl ketone (10 ml each). The solids were dried in a vacuum cabinet at 50 s,

From obtaining 4.86 g (81 95) of the desired product. The solid form from this procedure was characterized using the RCKO analysis and designated as form 2.

Convert form 2 to form 1

Form 2 (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-

M-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide (Example 1) (10.0 g, 24.6 mmol, 1.00 eq...), methyl ethyl ketone (8.8 ml/g), 88, 0 ml) and water (1.2 ml/g, 12.0 ml). The reactor was heated to 50°C for 30 minutes. Complete solution occurred at approximately 44°C. The reactor was cooled to 40 "C for 30 minutes, then the nuclei of the form 1 (5)-2-(5-((3-ethoxypyridin-2-yl)uoxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl) were loaded )pyrimidine-5-carboxamide (Example 1) (0.050 g, 0.123 mmol, 0.0050 equiv...). After seeding, the cloudy suspension was stirred for 1 hour before being cooled to 5 °C for 2 hours and then stirred at 5B "C for 12 hours. In the control process, a sample was collected and characterized using LCCO analysis to confirm that the solids were Form 1. The suspension was filtered, and the reactor and cake were washed with 0 "C methyl ethyl ketone (2.5 mL/g, 25 ml). The solids were dried in a vacuum oven at 50°C to yield 8.15 g (81.5 95) of the desired product.

The chromatograms of the desired product corresponded to form 1.

X-ray powder diffraction analysis:

Powder X-ray diffraction analysis was carried out using a diffractometer Vgykeg AX5 08 Aimapse, using a C radiation source (Ka - average wavelength 1.54056A), equipped with a double primary use of a tapestry mirror. The diffracted radiation was detected using a ROYOO-IIuph Euye detector. Both primary and secondary are equipped with 2.5 Soller slits. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a theta-theta goniometer in a fixed pair scan from 3.0 to 40.0 degrees 2-theta with 1000 steps, using a scan rate of b seconds per step. Samples were prepared by placing them on a silicone low-profile sample holder (С079298А32448261). Data were collected using the software VgykKeg OIREVAS Riv. The analysis was carried out using EMA Diffraction Plus software.

The RHVO data file was not processed prior to finding the peaks. Applying the peak search algorithm in

From the EMA software, peaks were selected with a threshold value of 5 and a width value of 0.2. The output of the automated tasks was checked visually for validity and adjusted manually if necessary. In total, peaks with a relative intensity of 2 out of 95 were selected. Peaks that were not resolved or were consistent with noise were also discarded. The typical error associated with the position of the peak from the РЧКО indicated in the OBR is within h/-0.27 (О5Р-941).

Table 1:

Key XAO peaks for the characterization of the crystalline substance from example 1

In Fig. 1 presents a characteristic powder X-ray diffraction pattern showing crystalline form 1 from example 1 (Vertical axis: Intensity (CRB);

Horizontal axis: Two theta (degrees)).

In Fig. 2 shows a characteristic powder X-ray diffraction pattern showing crystalline form 2 from example 1 (Vertical axis: Intensity (CRB);

Horizontal axis: Two theta (degrees)).

Example 2: (8n)-2-(5-(3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)upyrimidine-5-carboxamide and (c)

And S ty we MU

N

M

The title compound was prepared using general procedure A with intermediate 1 (0.31 mmol, 1.0 equiv) and (K)-(--)-tetrahydro-3-furylamine toluenesulfonate salt (124 mg, 1.5 equiv. ). The crude product was purified by flash chromatography using ethyl acetate in heptanes to afford (K)-2-(5-(3-ethoxypyridin-2-yl/oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl) upyrimidine-5-carboxamide (91 mg, 70 95). "H NMR (400 MHz, DMSO-av) 6 1.38 (t, ЗН), 1.89-1.98 (m, 1Н), 2.15-2.28 (m, 1Н), 3.5 (dd, 1H), 3.70-3.78 (m, 1H), 3.85-3.92 (m, 2H), 4.19 (q, 2H), 4.46-4.55 (m , 1H), 7.19 (dd, 1H), 7.58 (dd, 1H), 7.69 (dd, 1H), 8.37 (dd, 1H), 8.64 (d, 1H), 8 .96 (d, 1H), 9.28 (s, 2H), 9.39 (d, 1H). MS (ES. 408.3 (M'-H).

Examples 3.1 - 3.7: The examples in Table 2 were obtained by general procedure A, using the appropriate starting materials, and analyzed by the methods described below.

Short-circuit variables, intermediate compounds (which change to B", 0", and/or 0) were used, and the method of analysis is indicated in Table 2. cut (c)

And You Ge tuo Ya mya 2

M

Analytical methods:

Method A: Chbgidde C18, 2.1x50 mm, 5 μm, 40 "C, Mobile phase A 0.0375 95 TFO in water, Mobile phase B 0.01875 95 TFO in acetonitrile, Gradient: 0.00 min. 1 95 V , 0.60 min 5 Fo B, 4.00 min 100 95 V, 0.8 ml/min, АРИ-Е5-k.

Method B: XHgidde C18, 2.1x50 mm, 5 μm, 40 "C, Mobile phase A 0.05 95 MNAOH in water, Mobile phase B 100 95 acetonitrile, Gradient 0.00 min. 5 95 V, 3.40 min 100 95 V, 0.8 ml/min, АРИ-Е5-к.

Method C: M/agteg5 AiMapii5 C18 4.6 x 50.5 μm, Mobile phase A: 0.05 95 TFO in water (vol./o06.);

Mobile phase B: 0.05 95 TFO in acetonitrile (vol./06.), Gradient: 95.0 95 NgO/5.0 95 Acetonitrile linear to 5 95 NgO/95 95 Acetonitrile in 4.0 min., NOI O at 5 95 NgO/95 95 Acetonitrile up to 5.0 min.

Flow: 2 ml/min.

Method Y: Umaieg5 KhVgidde C18 4.6 x 50.5 μm, Mobile phase A: 0.03 95 MNAON in water (vol./06.);

Mobile phase B: 0.03 95 MNAOH in acetonitrile (vol./o6.), Gradient: 95.0 95 NgO/5.0 956 Acetonitrile linear to 5 95 NgO/95 95 Acetonitrile in 4.0 min., retention at 5 95 H20/95 95 Acetonitrile up to 5.0 min. Flow: 2 ml/min.

Method E: Hiitaige C18 5 x 30 mm, Z μm

Z Mobile phase A: 0.1 956 TFO in water, Mobile phase B: acetonitrile, Gradient: 0.00 min. 1 95 V, 1 min. 5 95 V, 5 min. 100 95 V, 8 min. 1 95 V. Flow rate: 1.2 ml/min.

Method E: LC-MS E(4-302) HVgidde C18 2.1750 mm, 5 μm

Mobile phase: 1.0 95 acetonitrile in water (0.1 96 formic acid) to 5 95 acetonitrile in water (0.1 96 formic acid) in 0.6 min.; then from 5.0 95 acetonitrile in water (0.1 96 formic acid) to 100 95 acetonitrile (0.1 96 formic acid) in 3.4 minutes; then again to 1.0 Fo acetonitrile in water (0.1 96 formic acid) for 4.3 min., and hold for 0.7 min. Flow rate: 0.8 ml/min.

Method C: Xbgidde C18, 2.0x50 mm, 5 μm, 40 "С, Mobile phase A 10 mm MNANSO: in water,

Mobile phase B 100 95 acetonitrile, Gradient from 1.095 V to 595 V in 0.6 min., 10095 V in 3.4 minutes; then again to 1.0 95 V within 0.3 min. Flow rate: 0.8 ml/min.

Table 2

Mo number Retention time of the compound MAN) (analytical method 2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3- o 3 methyl-1,1- - 4 470 2.310 dioxidotetrahydrothiophene Method C

Z-yl)pyrimidine-5-carboxamide

M-(1,3-dihydroxy-2-methylpropan-2-yl)-2-(5-3.2 ((3-ethoxypyridin-2-one 4,426 1,683 yl)oxy)pyridin-3-zone Method O yl)pyrimidine-5-carboxamide

M-(1,1-dioxidotetrahydrothiophene) 3.3 Z-yl)-2-(5-((3-y 4 456 3,319 ethoxypyridin-2-yl)oxy)- Х o Method E pyridin-3-yl)pyrimidine -5-carboxamide (5)-3-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-3.4 (tetrahydrofuran-3-yl)-50; 2 409 svv E 1,2,4-triazin-6-H carboxamide 2-(5-(3-ethoxypyrazin-2-3.5 | yl)oxy)pyridin-3-yl)-M-(1- z lon Z di 2.274 hydroxy-2-methylpropane-2- Method C yl)upyrimidine-5-carboxamide 2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(2-3.6 methyl-1 - o,,0 and 472 2,548 (methylsulfonyl)propane- C Method E 2-yl)pyrimidine-5-carboxamide (5)-2-(5-(3-(2-fluoroethoxy)pyridin-2-3.7yl)oxy )pyridin-3-yl)-M-C 2.325 (tetrahydrofuran-3-ych 2 4 425.9 Method E yl)pyrimidine-5-H carboxamide

Example 4: M-(2-cyanopropan-2-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidin-5-carboxamide

Y i M yo YAM tour SM more

M

The title compound was obtained by general procedure B with intermediate 1 (1.0 g, 1.0 equiv) and 2-amino-2-methylpropionitrile (436 mg, 1.1 equiv). The crude product was purified by flash chromatography (50-100 95 ethyl acetate in heptanes) and triturated with charcoal. The resulting residue was recrystallized from ethyl acetate (8 mL) to give N-(2-cyanopropan-2-yl)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)/pyrimidine -5-carboxamide (1.1 g, 92 95) as a colorless solid. "H NMR (400 MHz, DMSO-av) b 1.38 (t, ЗН), 1.74 (s, 6Н), 4.18 (q, 2Н), 7.18 (dd, 1Н), 7, 57 (dd, 1H), 7.69 (dd, 1H), 8.38 (dd, 1H), 8.66 (d, 1H), 9.18 (w s, 1H), 9.30 (s, 2H), 9.40 (d, 1H). MS (EC) 405.3 (INN).

Example 5: 2-(5-(3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(1-hydroxy-2-methylpropan-2-yl)upyrimidine-5-carboxamide

I Y it M ura

N

-

M

The title compound was obtained by general procedure A with intermediate 1 (260 mg, 1.0 equiv) and 2-amino-2-methylpropan-yl-ol (103 mg, 1.5 equiv). The crude product was purified by flash chromatography (50-100 90 ethyl acetate in heptanes) and recrystallized from ethyl acetate:methanol to give 2-(5-(3-ethoxypyridin-2-yl)uoxy)pyridin-3-yl)-M-( 1-hydroxy-2-methylpropan-2-yl)pyrimidine-5-carboxamide (236 mg, 7595) as a colorless solid. "H NMR (400 MHz, DMSO-av) b 1.33 (s, 6H), 1.38 (t, ЗН), 3.55 (d, 2Н), 4.18 (q, 2Н), 4, 83 (t, 1H), 7.18 (dd, Hz, 1H), 7.58 (d, 1H), 7.70 (d, 1H), 8.04 (w s, 1H), 8.34- 8.37 (m, 1H), 8.64 (d, 1H), 9.22 (s, 2H), 9.39 (d, 1H). MS (EC .yu) 410.3 (M--H ).

Example 19.21 in MO2015140658. This significant reduction in clearance is much greater than would be predicted by the given difference in the structures and values of ОСАТa2 ISzho from example 5 and example 19.21 from M/O2015140658.

Table C

Efficacy of OSATaZ and metabolic clearance in NI M

Si, arr

An example of Mo The structure of the genus ISvo in NIM

I (nMI μl/min./mg

And Y

AM M dream

Example 5 7to tu 14 18

GF) se

Io "-

M

Hm. he

UOhoi 5140658 177 mim 79 124

Example 19.21 about A. N' a

Examples ba and br: (K)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)pyrimidin-5- carboxamide and (5)-2-(5-(3-ethoxypyridin-2-yl)uoxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)/pyrimidin-5-carboxamide o ia y, rev: tu YN

H o) with Zm -

M

The title compounds were prepared using general procedure A with intermediate 1 (840 mg, 1 equiv) and (3-aminotetrahydrofuran-3-yl)methanol (320 mg, 1.1 equiv). The crude product was passed through a layer of silicon oxide, obtaining the racemate in the form of a yellow solid, which was separated using chiral purification 5ES: Chiral Tesi AB-N 250 mm x 4.6 mm B5mk;

Isocratic 70 95 A: carbon dioxide; Mobile phase at 30 95 V: 0.2 95 isopropylamine in isopropanol (vol./o06.). Flow: bOml/min.; background pressure - 120 bar. The first peak eluted from the column is example b, and the second peak is example 6b.

Enantiomer 1: 5EC retention time - 9.31 minutes. (330 mg) This compound was further purified by column chromatography (methanol in dichloromethane), then recrystallized from methanol in ethyl acetate to give enantiomer ba (218 mg, 20 95) as a colorless solid. "H NMR (400 MHz, COzObr) b 1.40 (t, ЗН), 2.23 (dt, 1Н), 2.29 - 2.37 (m, 1Н), 3.82 - 3.91 (m , 2H), 3.92 - 3.95 (m, 2H), 3.96 - 4.04 (m, 2H), 4.17 (q, 2H), 7.19 (dd, 1H), 7, 52 (dd, 1H), 7.71 (dd, 1H), 8.49 (dd, 1H), 8.52 (d, 1H), 9.22 (c, 2H), 9.41 (d, 1H ).MS (EU) 438.3 (INN).

Enantiomer 2: EC retention time - 9.59 minutes (300 mg). This compound was further purified using column chromatography (methanol in dichloromethane) then recrystallized from methanol in ethyl acetate to give enantiomer 65 (205 mg, 19 95) as a colorless solid. "H NMR (400 MHz, COzOb) 56 1.40 (t, ЗН), 2.23 (dt, 1Н), 2.29 - 2.37 (m, 1Н), 3.82 - 3.91 (m , 2H), 3.92 - 3.95 (m, 2H), 3.96 - 4.04 (m, 2H), 4.17 (q, 2H), 7.19 (dd, 1H), 7, 52 (dd, 1H), 7.71 (dd, 1H), 8.49 (dd, 1H), 8.52 (d, 1H), 9.22 (c, 2H), 9.41 (d, 1H ).MS (EU) 438.3 (M.N).

Example 7: 3-5-(3-ethoxypyridin-2-yl)oxy|pyridin-3-yl)-M-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-triazin-6 -carboxamide

F I lo on i

M

The title compound was prepared according to general procedure A using intermediate 2 (15 mg, 0.04 mmol) and 2-amino-2-methyl-1-propanol (4.73 mg, 0.053 mmol). The crude product was purified using preparative reversed-phase HPLC to afford the title compound (2.8 mg, 16 95) as a pale yellow solid. "H NMR (400 MHz, COzOb) b 1.40 (t, ЗН), 1.47 (s, 6Н), 3.70 (с, 2Н), 4.16 (q, 2Н), 7.20 ( dd, 1H), 7.53 (dd, 1H), 7.71 (dd, 1H), 8.56-8.58 (m, 1H), 8.61 (d, 1H), 9.32 (s , 1H), 9.48 (d, 1H). MS (EC kyu) 411.0 (MN).

Example 8: (5)-2-(5-(3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)upyrimidine-5-carboxamide

And: (about) what; Ho that - M and more

M

From Stage 1: 3-Ethoxy-5-fluoropyridine-1-oxide

Cesium carbonate (21.6 g, 3.0 equiv.) was added to a solution of 5-fluoro-3-pyridinol (25 g, 1.0 equiv.) and ethyl iodide (3.8 g, 1.1 equiv.). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered and concentrated to give 3-ethoxy-5-fluoropyridine (3.1 g, 10095) as a yellow oil, which was used without further purification. m-

Chloroperoxybenzoic acid (5.7 g, 1.5 equiv) was added to a solution of 3-ethoxy-5-fluoropyridine (3.1 g, 1.0 equiv) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by direct flash chromatography (gradient: 0-595 methanol in dichloromethane) to give 3-ethoxy-5-fluoropyridine-1-oxide (3.30 g, 95 95) as a white solid. "H NMR (400 MHz, COzOb) b 1.40 (t, ЗН), 4.14 (sq, 2Н), 7.20 (dt, 1Н), 7.96-7.98 (m, 1Н), 8.04-8.08 (m, 1H).

Stage 2: 2-(5-Bromopyridin-3-yl)oxy)-3-ethoxy-5-fluoropyridine

Diisopropylethylamine (3.08 g, 3.8 equiv) was added to a solution of 3-ethoxy-5-fluoropyridine-1-oxide (1.0 g, 1.0 equiv) and bromotripyrrolidinophosphonium hexafluorophosphate (3.86 g, 1, 3 equiv.) in tetrahydrofuran (60 ml) at 0 "C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (150 ml) and extracted with ethyl acetate (3 x 50 ml).

The combined organic layers were washed with saturated saline (100 mL), dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (gradient: 4-24 95 ethyl acetate in petroleum ether) to give 2-((5-bromopyridin-3-yl)oxy)-3-ethoxy-5-fluoropyridine (200 mg, 10 95 ) in the form of a white solid.

NMR NMR (400 MHz, SOSIZ) b 1.48 (t, ЗН), 4.12 (q, 2Н), 7.04 (dd, 1Н), 7.56-7.59 (m, 1Н) , 7.66-7.67 (m, 1H), 8.41-8.42 (m, 1H), 8.48-8.50 (m, 1H).

Stage C: Ethyl 2-(5-(3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate

Bis(pinacolatoduboron (243 mg, 1.2 eq.), potassium acetate (235 mg, 3.0 eq.), and (P,1- bisidiphenylphosphino)ferrocenedichloropalladium(II) complex with dichloromethane (29 mg, 0.05 eq. ) was added to a solution of 2-(5-bromopyridin-3-yl)oxy)-3-ethoxy-5-fluoropyridine (250 mg, 1.0 equiv.) in dioxane (5 mL) at room temperature. The reaction mixture was stirred at 100 "C for 2 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (60 mL) and filtered through celite. The filtrate was concentrated to a residue then diluted with dioxane (5 mL) and water (1 mL). Ethyl 2 -chloropyrimidine-5-carboxylate (164 mg, 1.1 equiv.), 1,1-bisidiphenylphosphino)ferrocene|dichloropalladium(II) complex with dichloromethane (18 mg, 0.03 equiv.), and potassium carbonate (166 mg, 1.5 equiv.) was added to the reaction mixture, and the resulting suspension was stirred at 80 "C for 2 hours, then allowed to stand at room temperature for 4 days. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layer was separated, washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give a crude material which was purified by preparative TLC (5:11 petroleum ether:ethyl acetate) to give ethyl 2-(5- (3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylate (50 mg, 16 95). MS (EC k) 385.0 (M--H).

Step 4: 2-(5-(3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxylic acid

Sodium hydroxide (0.20 mL, 3.0 equiv., 2M) was added to ethyl 2-(5-(3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-o-carboxylate (50 mg, 1.0 equiv.) in ethanol (10 mL). The reaction mixture was stirred at 25 "C for 16 hours. The solution was diluted with water (50 ml) and extracted with ethyl acetate (3 x 30 ml). The aqueous layer was acidified with hydrochloric acid (2M) to pH 3.

The solution was extracted with ethyl acetate (15 mL), dried over sodium sulfate, and concentrated,

Z to give 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)/oxy)pyridin-3-yl)pyrimidine-o-carboxylic acid (25 mg, 54 95) as a yellow solid. MC (EC) 357.0 (MAN).

Step 5: (5)-2-(5-(3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)upyrimidine-5-carboxamide

The title compound was prepared according to general procedure A using 2-(5-((3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)/pyrimidine-5-carboxylic acid (25 mg, 1, 0 equiv) and (5)-tetrahydrofuran-3-amine (18.3 mg, 3.0 equiv). The crude material was purified using preparative HPLC to give (5)-2-(5-(3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidin- 5-carboxamide (20 mg, 67 95) as a white solid. "N

NMR (400 MHz, DMSO-46) 5 1.38 (t, ЗН), 1.87 - 2.00 (m, 1Н), 2.14 - 2.28 (m, 1Н), 3.65 (dd , 1H), 3.70 - 3.79 (m, 1H), 3.83 - 3.94 (m, 2H), 4.21 (sq, 2H), 4.46 - 4.56 (m, 1H ), 7.65 - 7.74 (m, 2H), 8.37 (dd, 1H), 8.65 (d, 1H), 8.98 (d, 1H), 9.29 (s, 2H) , 9.40 (d, 1H). MS (EU) 425.9 (M.N).

PHARMACOLOGICAL DATA

The following protocols can usually be modified by one skilled in the art.

Obtaining the human construct OBAT2 (POSAT2)

The POSAT2 construct was obtained with an M-terminal RAS tag (octapeptide with the amino acid sequence AzrtTuguzA5zraA5raAb5rAvzri uz). For the BAS-labeled POSAT2 construct, the cDNA for POSATaO was custom-made by Sepvsgiri and cloned into the rEaseVas1 vector (Ipmigodep) using the restriction enzymes VatNi/XpoI, yielding an M-terminally RGASb-labeled construct rEaseVas1-P and pOAT2 (amino acids 1- 388).

The construct was confirmed by sequencing in both directions.

Expression of OSAT2 and preparation of the OSAT2 membrane fraction

Recombinant baculovirus for RI Ab-tagged POSAT2 was produced in 5E9 insect cells using the Vas-you-Vas baculovirus expression system (Ipmigodep) according to the manufacturer's protocol. For pPOSAT2 expression, 5EU cells (20 L) grown in medium 519001 were infected with pPOSAT2 baculovirus at multiple infection 1 in an Umame wave package

Viogeasiog Zuziet 20/50R (SE Neaisage). After 40 hours of infection, cells were then harvested by centrifugation at 5000 x 4. Cell pellets were washed by resuspension in phosphate buffered saline (PB5) and harvested by centrifugation at 5000 x 4.

The cell paste was flash-frozen with liquid M? and stored at -80 "C until needed. All operations mentioned below were carried out at 4 "C, unless otherwise indicated. Cells were resuspended in lysis buffer (50 mM Tris-HCl, pH 8.0, 250 mM sucrose) containing 1 mM ethylenediaminetetraacetic acid (EDTO) and complete protease inhibitor cocktail (Cospe

Riadpowiis5) with a ratio of 3 ml of buffer per 1 g of cell paste. Cells were lysed using a Downs homogenizer. Cell debris was removed by centrifugation at 1000 x d for 20 min, and the supernatant was centrifuged at 100,000 x d for 1 hour. The resulting pellet was washed three times by filling ultracentrifugation tubes to the top with ice-cold PB5 and subsequent decantation.

The washed pellet was resuspended with gentle agitation for 1 hour in lysis buffer containing 8 mM 3-(3-cholamidopropyldimethylammonium)|-1-propanesulfonate (SNARBZ) at a ratio of 1 mL of buffer per 1 g of initial cell paste and centrifuged again at 100 000 x d for 1 hour. The resulting supernatant was divided into aliquots, quickly frozen in liquid M" and stored at -80 "C until use.

Ip Migo studies OSAT?2 and determination of ISbho values for OSAT2 inhibitors

To determine IC values, the reactions were carried out in a 384-well white Roiuria 5 plate (Regkip EITeg) in a total volume of 20 μl. 5 μl of 0.04 95 calf serum albumin (B5A) (free from fatty acids, 5idta Aiagisp) was added to 1 μl of compounds dissolved in 100 95 DMSO and applied dropwise to the bottom of each well, and the mixture was incubated at room temperature for 15 minutes . Fractions of POSAT2 membranes were diluted in 100 μM Nere5-maon, pH 7.4, 20 μM Masi'', containing 200 nM methylarachidonyl fluorophosphonate (Soutap Spetisai; dried from the ethyl acetate stock solution under an atmosphere of gaseous argon and dissolved in DMSO as a 5 mM stock solution). 10 μl of the working solution of this enzyme was added to the tablets and the incubation was continued for 2 hours at room temperature. OSAT2 reactions were initiated by adding 4 μl of substrates containing 30 μM (1-"C|decanoyl-CoA (synthesized by order of Regkip EITeg, 50 mCi/mmol) and μM 1,2-didecanoyl-5p-glycerol (Amapii Royag I iriad5 ), dissolved in 12.5 95 acetone. The reaction mixtures were incubated at room temperature for 40 min., and the reactions were stopped by adding 5 μl of 1 95 NzPOx. After adding 45 μl of Misgossypi-E (ReiZhKip-EIteg), the plates were hermetically covered with Tor zZeAl lids -A (ReiKkip-Eiteg) and achieved phase separation of substrates and products using an NT-91100 microplate orbital shaker (Ved Veag Ashotaiyop, Zapia Siaga, CA).

The tablets were centrifuged at 2000 x d for 1 min. on a APeaga 6A Sepigpide centrifuge (VesKtap SoshiMeg), and sealed again with fresh lids before reading in a scintillation counter 1450 Misgobeia MMaPyas Tgyykh ZsipiShanop Soypieg (RegKkip EIteg).

The activity of USAT2 was measured by determining the amount of the product formed

G"STgridecanoylglycerol in the upper organic phase.

Background activity obtained using 50 μM (K)-1-(2-((5)-1-(4-chloro-1H-pyrazol-1-yl)ethyl)-ZN-imidazo|4,5-b| pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)umethanone (MMO 2013150416,

Example 196-A) for complete inhibition of OSyaAT2, was subtracted from all reactions. Inhibitors were tested at eleven different concentrations to obtain IC values for each compound. The eleven inhibitor concentrations used typically included 50, 15.8, 5, 1.58, 0.50, 0.16, 0.05, 0.016, 0.005, 0.0016, and 0.0005 µM. The data were plotted as percentage of inhibition versus inhibitor concentration and fitted to the equation, y-100/L1 i (x/ICo)i, where ICvo is the inhibitor concentration at 50 95 inhibition and 7 is the Hill slope (the slope of the curve at its inflection point) . Table 4 below lists the IC values of examples for inhibition of USBAT2 according to the analysis described above. The results are given as the geometric mean

IT

Table 4. IS values of examples for inhibition of raAT2 ba 17777111 209 DU 11166711 232 81111113

Determination of ISbzo values for OSAT2 inhibitors in human hepatocytes

In order to evaluate the action of USAT2 inhibitors in a cell-based study, cryopreserved human hepatocytes (ои МОМ and ЕВ5, Сей5и5, Spisado, I) were thawed and applied to collagen-coated tablets of the type | according to the manufacturer's instructions. After a 24-hour recovery period, cells were plated with medium containing 250 μg/ml Maihide! (VO

Viozsiepse5, Zap ChShdoze, SA). The next day, the medium was aspirated and replaced with serum-free Williams E medium (I She TesppoiYodie5, sgapa Ivziapa, MU) and containing 400 μM sodium dodecanoate (5idta-Aiagisp, 51. Ioci5, MO). After forty-five minutes, the selective inhibitor OSATI (Example 3, M/O2009016462, obtained as 100X stock solutions in 2595 DMSO, 7595 Williams medium E) was added to all wells to a final concentration (3 µM) that completely inhibited endogenous activity of WASP1. Then, USAT2 inhibitors were added to the desired final concentration. After 15 minutes of pre-incubation, 0.2 µCi (1,3-2C1-glycerol (Ateguisap Cadio Spetis!5,

ZI. Gotsi5, MO) followed by incubation for 3 hours. After that, the medium was removed, the cells were washed once with RVB5 and then lysed in a mixture of isopropyl alcohol:tetrahydrofuran (9:1) before centrifugation at 3000 rpm for 5 minutes. Radiolabeled lipids were separated using a 2-solvent system by thin-layer chromatography with solvent 1 consisting of ethyl acetate: isopropyl alcohol: chloroform: methanol: 0.25 95 potassium chloride in water (100:100:100:40.2: 36.1, vol./vol./06./06.) and solvent 2, which consists of hexane: diethyl ether: acetic acid (70:27:3, vol./o06./06.)). TLC plates were developed in solvent 1 to a third of the plate height, the plate was dried under nitrogen and then developed to the top plate. After separation, radioactively labeled lipids were visualized using the Rpozrpogitadeg Moiesschag Bupatis5 system. Half-maximal inhibitory concentrations (ICvho values) were determined using SgarpRaid Rgist (sgarpRaid Boiimage, Ips., Ha doPa, CA) using the Hill function with a fixed baseline of 0 (vehicle control) and a Hill slope of 1.

In this setting, Example 1 showed a geometric mean IC value of 2.8 nm (M-10).

Effects of OCATZ2 inhibitors on plasma and hepatic triglyceride levels

To assess the long-term effects of OSAT2 inhibitor treatment on plasma triglyceride production and hepatic triglyceride content, a western diet rat model was used. Male Sprague-Dawley rats were housed under standard laboratory conditions with a 12-hour light, 12-hour dark cycle (light on at 06:00). Two weeks before the start of the study, the animals were placed on a high-fat, high-cholesterol diet (0120790, Kezeagsp Oieyi5, Mem/ VgypbulsK, MO). This diet provides - 43 95 kilocalories from carbohydrates and «- 41 95 kilocalories from fat. OSAT2 inhibitors were administered orally as a solution (10 ml/kg dosage volume) in 0.5 925 НРМСА5Б-НЕ and 0.01595 515 in bi-water, pH 8.5 (methylcellulose and butylated hydroxytoluene were obtained from Bidta Aiagisp, 51 Iotsiv,

MO). Animals treated with the carrier received an aqueous solution of 0.5 95 NRMSAZB-NE and 0.015 95 51 5 in 0I water, pH 8.5, separately. OSAT2 inhibitors were administered orally twice daily for 7 days at 08:00 and 16:00 at 1, 3, 10, 30, and 90 mg/kg. On day 8, all animals were fasted at 06:00, dosed with vehicle or OSAT2 inhibitors at 10:00, and euthanized 2 hours after dosing.

Rats were euthanized by carbon dioxide asphyxiation, and blood was collected via the lateral tail vein. TO levels in plasma were determined using the Cospe Niaspi analyzer

Spectivig was performed according to the manufacturer's instructions (Kospe Oiadpowiis5 Sogrogayop, Ipaiaparoiiv, IM) and data were analyzed using sgarpRay Rgist (SsgarpRai Zoiymage, Ips., Ga UdoMa, SA). Collection of liver samples to determine the content of triglycerides in the liver was excised during euthanasia, immediately frozen in liquid nitrogen and stored at -807 C until analysis. To estimate the level of triglycerides in the tissue of the liver section wrapped in aluminum foil, it was crushed with a hammer on an aluminum heat block in a bath with liquid nitrogen. Pulverization of liver tissue gave a homogeneous powder. Homogenization buffer, Tgi5 pH 7.4, 98.9 ml 0.9 95 Mass and 100 μl Tgyop

X 100, mixed on a stir plate for 10 minutes before use. Sample masses of approximately one hundred milligrams of homogenous liver tissue were weighed and placed in a test tube

I was mixed with 1 mL of homogenization buffer. All samples were then placed in a RahziRger EP120 (MR Vioteadisai5, Sai Zh 6001-1200) for 2 minutes or until the tissue was properly homogenized. All samples were then spun for 30 seconds at 10,000 rpm to defoam the homogenization. 50 microliters of the sample was transferred to a sterile mixing plate with 450 microliters of Dulbecco's phosphate-buffered saline (PBS5) to create a 1:10 dilution. After resuspending a fresh sample, all samples were transferred to sample tubes for the bietep5 clinical analyzer

Adma Khrt. Triglyceride analysis was performed by absorption and reported as milligrams per deciliter. Triglycerides were then normalized per gram of tissue in Mysgozoia Echsei|.

Fig. With and Fig. 4 summarizes the effects of oral administration from Example 1 on plasma and hepatic triglyceride levels in Sprague-Dawley rats fed a Western diet as described above. Data are the mean “with standard deviation” of 8 animals. The difference between the average values in the groups in relation to the carrier was carried out using 1-factor analysis of variance of AMOMA followed by Dunnett's multiple comparisons test "р"k0.01, и7"р-0.0001.

Various publications are mentioned throughout this application. The disclosures of these publications in their entirety are hereby incorporated into this application by reference for all purposes.

It will be apparent to one skilled in the art that various modifications and variations of the invention may be made without departing from the scope and spirit of the invention. Other embodiments will be apparent to one skilled in the art upon review of the description and experimental portion of the invention disclosed herein. It is obvious that the description and examples are to be considered as illustrative only, the precise scope and spirit of the invention being disclosed in the following examples.

Claims (23)

FORMULA OF THE INVENTION 1. Compound of Formula (1): ryn" o Zh z a gm "M sa y ge i s B y t h ! AI this M; (I) wherein p" and R0- are each independently M or CH; B' is H or (C:-C8)alkyl, optionally substituted with one or two substituents, each independently selected from fluorine and (C3-C8) cycloalkyl; B2 is H or fluorine; x to : sh ra o XX r x sklkn x i; more uzo What kt o x 4 BZ is K ; Kk or 7" K ; B" is H, cyano or (C:-Ca )alkyl, optionally substituted with one or two substituents, each independently selected from -OH and -5(0)2H5; Vo is H or -OH; and Be is (Ci-Ca)alkyl; or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1 of Formula (Ia) also Y and Z dito M gu "ek 0. with M H also M (z) or its pharmaceutically acceptable salt. like 90; x i - ! and x where 3. The compound according to claim 1 or its pharmaceutically acceptable salt, in which KZ is: . ro 4. The compound according to claim 1 or its pharmaceutically acceptable salt, in which KZ is Y 5. The compound according to item C or its pharmaceutically acceptable salt, in which K' is methyl. 6. The compound according to claim 4 or its pharmaceutically acceptable salt, in which K' is methyl. 7. The compound according to claim 6 or its pharmaceutically acceptable salt, in which K" is H, -СНоОН or cyano. 8. The compound of Formula (I) selected from the group consisting of: (5)-2-(5-(3-ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-M-( tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; M-(2-cyanopropan-2-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)upyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrimidin-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)upyrimidine-5-carboxamide; (8)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)upyrimidine-5-carboxamide; 2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(2-methyl-1-(methylsulfonyl)propan-2-yl)upyrimidine-5-carboxamide; (5)-2-(5-(3-(2-fluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; 3-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-triazin-6- carboxamide; M-(1,3-dihydroxy-2-methylpropan-2-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidin-5-Co)carboxamide; (5)-3-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-1,2,4-triazin-6-carboxamide; M-(1,1-dioxidotetrahydrothiophen-3-yl)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide; (8)-2-(5-(Z-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide or 2-(5-((Z -ethoxypyrazin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrimidine-5-carboxamide; or a pharmaceutically acceptable salt thereof. 9. The compound of Formula (I) selected from the group consisting of: (8)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl) )tetrahydrofuran-3-yl)upyrimidine-5-carboxamide; (5)-2-(5-(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide or (5)-2-(5 -(3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-M-(3-(hydroxymethyl)tetrahydrofuran-3-yl)upyrimidine-5-carboxamide, or its pharmaceutically acceptable salt. 10. Compound of Formula (I), which has the structure: o a shu ! NBM with or its pharmaceutically acceptable salt. 11. A pharmaceutical composition containing a compound according to claim 1 or a pharmaceutically acceptable salt of this compound, present in a therapeutically effective amount, in admixture with at least one pharmaceutically acceptable excipient. 12. The composition of claim 11, further comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-inflammatory agent, an anti-diabetic agent, and a cholesterol/lipid modulating agent. 13. The composition according to claim 12, in which the specified additional pharmaceutical agent is selected from the group consisting of an acetyl-CoA-carboxylase (ACC) inhibitor, a diacylglycerol O-acyltransferase 1 (DAC-1) inhibitor, monoacylglycerol O-acyltransferase inhibitors, an inhibitor phosphodiesterase (POE)-10, AMPK activator, sulfonylurea, meglitinide, c-amylose inhibitor, o-glucoside hydrolase inhibitor, o-glucosidase inhibitor, РАКУ agonist, РРАБК agonist s/u, biguanide, modulator of glucagon-like peptide 1 (SI P-1) , liraglutide, albiglutide, exenatide, albiglutide, lixisenatide, dulaglutide, semaglutide, protein tyrosine phosphatase-1B (PTP-1B) inhibitor, 5IKT-1 activator, dipeptidyl peptidase IM (ORP-IM) inhibitor, insulin secretion stimulator, fatty acid oxidation inhibitor, A2 antagonist , inhibitor of c-Y0p amino-terminal kinases (MK), glucokinase activators (SKa), insulin, insulin mimetic, glycogen phosphorylase inhibitor, MPAS2 receptor agonist, ZO 2 inhibitors, mod glucagon receptor modulators, SRK119 modulators, derivatives or analogs of EOE21, TOK receptor modulators, SRVACT receptor modulators, SORK40 agonists, Zo OSPE120 modulators, nicotinic acid receptor activators with high affinity (NM74A), ZOBI 11 inhibitors, inhibitors or modulators of carnitine palmitoyltransferase enzymes, inhibitors fructose-1,6-diphosphatase, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TOKS2 inhibitors, CSK2 and/or CSK5 inhibitors, PKS isoform inhibitors (for example, РКСо, РКСрР, РКСУ), fatty acid synthetase inhibitors, serine palmitoyltransferase inhibitors, modulators of ORK81I, СРКЗ9, ORK43, ORK41, SRK105, Km1.3, retinol-binding protein 4, glucocorticoid receptor, somatostatin receptors, inhibitors or modulators of RONK2 or RONKUA, MARAK inhibitors, modulators of the I/1 family, including II 1-beta, reductase inhibitors of NMO- CoA, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ASAT inhibitors, MTP inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, modulators of RAZCUO, cholesteryl ester transfer protein inhibitors, and EKK-alpha modulators. 14. The composition according to claim 11, which additionally contains at least one additional pharmaceutical agent selected from the group consisting of cysteamine or a pharmaceutically acceptable salt thereof, cystamine or a pharmaceutically acceptable salt thereof, an antioxidant compound, lecithin, a vitamin B complex, bile salt preparations, antagonists of the cannabinoid receptor-1 (CVI), inverse agonists of the cannabinoid receptor (CB1), regulators of the activity of the peroxisome proliferator-activated receptor, benzothiazepine or benzothiepine compounds, RNA of the antisense construct for inhibiting the tyrosine phosphatase RTREKA, bound through the heteroatom of substituted piperidine and its derivatives , an azacyclopentane derivative capable of inhibiting the stearoyl coenzyme alpha-delta-9-desaturase, an acylamide compound that has a secretogenic or inducing activity of adiponectin, a quaternary ammonium compound, glatiramer acetate, pentraxin proteins, an inhibitor of HMO-CoA reductase, p-acetylcysteine, an isoflavone compound, macroglacial o antibiotic, galectin inhibitor, antibody or any combination thereof. 15. A method of reducing at least one parameter of the severity of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis classified by scoring systems, reducing the level of serum markers of non-alcoholic steatohepatitis activity, reducing the disease activity of non-alcoholic steatohepatitis or reducing the medical consequences of non-alcoholic steatohepatitis in humans, which includes the step of administering to a person, which in need of such reduction, an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt of the compound to a patient in need thereof. 16. A method of treating fatty degeneration of the liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma in humans, which includes the step of administering to a person in need of such treatment a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt of this compound. 17. Method of treatment of hyperlipidemia, type I diabetes, type I diabetes, idiopathic type I diabetes (type II), latent autoimmune diabetes in adults (ALA), early onset type 2 diabetes (EOB), atypical diabetes with onset in young age (MOAO), adult-onset diabetes in the young (MOYU), associated with wasting diabetes, gestational diabetes, ischemic heart disease, ischemic stroke, rostenosis after plastic surgery on vessels, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, states of impaired glucose tolerance (IST), states of impaired fasting plasma glucose, metabolic acidosis, ketosis, arthritis, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerulosclerosis, chronic kidney failure, dia betic neuropathy, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, stroke, vascular restenosis, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose metabolism disorders, erectile dysfunction, skin and connective tissue disorders, foot ulcers and nonspecific ulcerative colitis, endothelial dysfunction and impaired vascular compliance, hyper- or r-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, ulcerative colitis, Crohn's disease and irritable bowel syndrome, nonalcoholic steatohepatitis (MA5N) or non-alcoholic fatty liver disease (NAFLD) in humans, which includes the step of administering to a human in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt of this compound. 18. A method of treating fatty degeneration of the liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis with liver fibrosis, non-alcoholic steatohepatitis with cirrhosis or non-alcoholic steatohepatitis with cirrhosis and hepatocellular carcinoma in humans, which includes the step of administering to a person in need of such treatment a therapeutically effective the amount of two separate pharmaceutical compositions, including: () the first composition according to claim 12; and (a second composition thereof that contains at least one additional pharmaceutical agent selected from the group consisting of an anti-inflammatory agent, an anti-diabetic agent, and a cholesterol/lipid-modulating agent, and at least one pharmaceutically acceptable excipient. 19. The method according to claim 18, in which the specified first composition and the specified second composition are administered simultaneously. 20. The method according to claim 18, in which said first composition and said second composition are introduced sequentially and in any order. 21. The method according to claim 15, which reduces portal hypertension, the ability to synthesize liver proteins, hyperbilirubinemia or encephalopathy. 22. Crystalline form 1 of the compound having the structure: Shk Go) t tuyu «M tro A Zh o o Susk mi SHCHI M my os ro - M or its pharmaceutically acceptable salt, in which the powder X-ray diffractogram has the value 2-theta (SiCo; radiation, wavelength 1.540564A) 5 ,3:20.2, 7.70.2 and 15.4:50.2. 23. Crystalline form of compound 2, which has the structure: Shk Go) t shi | shk oz Z Ko - gus sny hi s KI k yak osro sche M or its pharmaceutically acceptable salt, in which the powder X-ray diffractogram has the value 2-theta (SiCo; radiation, wavelength 1.540564А) 6.5:0.2 , 9.3:20.2 and 13.6:50.2.